Sensitivity Of Cells Research Articles

Oxidative Phosphorylation as a Predictive Biomarker of Oxaliplatin Response in Colorectal Cancer.

Oxaliplatin is successfully used on advanced colorectal cancer to eradicate micro-metastasis, whereas its benefits in the early stages of colorectal cancer remains controversial since approximately 30% of patients experience unexpected relapses. Herein, we evaluate the efficacy of oxidative phosphorylation as a predictive biomarker of oxaliplatin response in colorectal cancer. We found that non-responding patients exhibit low oxidative phosphorylation activity, suggesting a poor prognosis. To reach this conclusion, we analyzed patient samples of individuals treated with oxaliplatin from the GSE83129 dataset, and a set of datasets validated using ROCplotter, selecting them based on their response to the drug. By analyzing multiple oxaliplatin-resistant and -sensitive cell lines, we identified oxidative phosphorylation KEGG pathways as a valuable predictive biomarker of oxaliplatin response with a high area under the curve (AUC = 0.843). Additionally, some oxidative phosphorylation-related biomarkers were validated in primary- and metastatic-derived tumorspheres, confirming the results obtained in silico. The low expression of these biomarkers is clinically relevant, indicating poor prognosis with decreased overall and relapse-free survival. This study proposes using oxidative phosphorylation-related protein expression levels as a predictor of responses to oxaliplatin-based treatments to prevent relapse and enable a more personalized therapy approach. Our results underscore the value of oxidative phosphorylation as a reliable marker for predicting the response to oxaliplatin treatment in colorectal cancer.

Extracellular vesicles in cancer drug resistance: Mechanistic insights and therapeutic implications

AbstractDespite significant advancements in the treatment of cancer, therapeutic resistance remains a major hurdle for the achievement of full cures. Besides being typically driven by intratumoral heterogeneity, such acquired resistance also relies heavily on cell‐cell communication whereby extracellular vesicles (EVs) carrying resistance‐related components can be transferred from drug‐resistant cells or nontumorigenic members within tumor microenvironment (TME) to their sensitive neighbors. The cargo and membrane surface proteins of EVs derived from drug‐resistant cells and TME cells carry abundant biological information, transferring therapy‐resistant capacity to sensitive cancer cells. Hence, a deep understanding of the roles of EVs in cancer therapy resistance will facilitate identifying biomarkers and developing new approaches to restore therapy sensitivity. In this review, we summarize our current understanding regarding the causes and effects of EV‐mediated cell–cell communication in drug resistance, with a particular notice on how various kinds of cargoes derived from different cells within TME are linked to the resistant phenotype. We also discuss how this knowledge can contribute to improvements in clinical practice, that is, the opportunities and challenges of EVs in functioning as potential biomarkers in predicting therapeutic resistance and, by extension, EV‐based therapy in achieving deeper and longer‐lasting clinical responses.

MYO6 contributes to tumor progression and enzalutamide resistance in castration-resistant prostate cancer by activating the focal adhesion signaling pathway

BackgroundEnzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear.MethodsMultiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated.ResultsMYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues − 503 to − 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models.ConclusionsMYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway.

Chlorella-enriched hydrogels protect against myocardial damage and reactive oxygen species production in an in vitro ischemia/reperfusion model using cardiac spheroids

Microalgae have emerged as promising photosynthetic microorganisms for biofabricating advanced tissue constructs, with improved oxygenation and reduced reactive oxygen species (ROS) production. However, their use in the engineering of human tissues has been limited due to their intrinsic growth requirements, which are not compatible with human cells. In this study, we first formulated alginate-gelatin (AlgGel) hydrogels with increasing densities ofChlorella vulgaris. Then, we characterised their mechanical properties and pore size. Finally, we evaluated their effects on cardiac spheroid (CS) pathophysiological response under control and ischemia/reperfusion (I/R) conditions. Our results showed that the addition ofChlorelladid not affect AlgGel mechanical properties, while the mean pore size significantly decreased by 35% in the presence of the 107cells ml-1microalgae density. Under normoxic conditions, the addition of 107Chlorellacells ml-1significantly reduced CS viability starting from 14 d in. No changes in pore size nor CS viability were measured for hydrogels containing 105and 106Chlorellacells ml-1. In our I/R model, allChlorella-enriched hydrogels reduced cardiac cell sensitivity to hypoxic conditions with a corresponding reduction in ROS production, as well as protected against I/R-induced reduction in cell viability. Altogether, our results support a promising use ofChlorella-enriched Alg-Gel hydrogels for cardiovascular tissue engineering.

Heparin-binding EGF-like growth factor: mechanisms of biological activity and potential therapeutic applications

The diphtheria toxin receptor on sensitive mammalian cells is known as the membrane anchored precursor of heparin-binding EGF-like growth factor (HB-EGF). When the precursor is cleaved by metalloproteinases, a soluble form (sHB-EGF) is formed that can bind to the EGF receptors, resulting in activation of signaling pathways that regulate cell proliferation, differentiation, migration, and inhibition of apoptosis. The ability of HB-EGF to cause both positive and negative consequences for organism underscores the complexity of its biological functions and the need for a nuanced understanding of its role in health and disease. In this review the data on the HB-EGF structure, biological activity, involvement in the mechanism of diphtheria toxin action, wound healing, tumor progression as well as the methods of HB-EGF delivery are summarized. Keywords: cell proliferation, diphtheria toxin, EGF receptor, heparin-binding EGF-like growth factor, signal transduction, wound healing

Pericytes Modulate Third-Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR-Mutated Lung Cancer Cells Through IL32-β5-Integrin Paracrine Signaling.

EGFR-mutated lung cancer patients sometimes display restricted responses to third-generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR-mutated patients have a unique secretome profile, notably secreting IL32 and affecting signaling pathways and biological processes linked to TKI sensitivity. Clinical evidence, supported by single-cell RNA sequencing and multiplex immunostaining of tumor tissues, confirms the presence of IL32-expressing pericytes closely interacting with β5-integrin-expressing cancer cells in EGFR-mutated patients, impacting therapeutic response and prognosis. Co-culture and conditioned medium experiments demonstrate that PCs reduce TKI effectiveness in EGFR-mutated cancer cells, a reversible phenomenon through silencing IL32 expression in PCs or depleting the IL32 receptor β5-integrin on cancer cells, thereby restoring cancer cell sensitivity. Mechanistically, it is shown that YY1 signaling upregulates IL32 secretion in PCs, subsequently activating the β5-integrin-Src-Akt pathway in EGFR-mutated cancer cells, contributing to their TKI sensitivity. In animal studies, co-injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5-integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32-β5-integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR-mutated patients.

Terpenoids from quinoa reverse chemoresistance in breast cancer by suppressing the stemness‐related lncRNA 667012

AbstractChemoresistance is a major cause of breast cancer (BC) recurrence and metastasis, and chemotherapy resistance comes from tumor stemness. Our previous study showed that quinoa bran terpenoids (QBT) exhibited significant antitumor activity. In this study, we found that QBT increased the sensitivity of drug‐resistant BC cells to the chemotherapeutic drugs adriamycin (ADR) and taxol (TAX). A novel lncRNA 667012 was identified along with QBT treatment. Moreover, overexpression of lncRNA 667012 promoted drug resistance, and the reduction of 667012 restored the drug sensitivity of resistant BC cells. More importantly, the findings revealed that lncRNA 667012 promoted stemness maintenance via the stemness‐related Wnt pathway. Furthermore, the result showed that QBT reduced 667012 expression and inhibited the activation of β‐catenin, thereby attenuating the stemness characteristics of BC and enhancing chemosensitivity. Consistently, the data were confirmed in the xenograft mice model. These results suggest that QBT could reverse chemoresistance by inhibiting stemness. It has the potential to be developed as a novel chemotherapeutic agent or chemosensitizer for BC treatment.

Endogenous Magnetic Lipid Droplet-Mediated Cascade-Targeted Sonodynamic Therapy as an Approach to Reversing Breast Cancer Multidrug Resistance.

Multidrug resistance (MDR) has emerged as a major barrier to effective breast cancer treatment, contributing to high rates of chemotherapy failure and disease recurrence. There is thus a pressing need to overcome MDR and to facilitate the efficient and precise treatment of breast cancer in a targeted manner. In this study, endogenous functional lipid droplets (IR780@LDs-Fe3O4/OA) were developed and used to effectively overcome the limited diffusion distance of reactive oxygen species owing to their amenability to cascade-targeted delivery, thereby facilitating precise and effective sonodynamic therapy (SDT) for MDR breast cancer. Initially, IR780@LDs-Fe3O4/OA was efficiently enriched within tumor sites in a static magnetic field, achieving the visualization of tumor treatment. Subsequently, the cascade-targeted SDT combined with the Fenton effect induced lysosome membrane permeabilization and relieved lysosomal sequestration, thus elevating drug concentration at the target site. This treatment approach also suppressed ATP production, thereby inhibiting P-glycoprotein-mediated chemotherapeutic drug efflux. This cascade-targeted SDT strategy significantly increased the sensitivity of MDR cells to doxorubicin, increasing the IC50 value of doxorubicin by approximately 10-fold. Moreover, the cascade-targeted SDT also altered the gene expression profiles of MDR cells and suppressed the expression of MDR-related genes. In light of these promising results, the combination of cascade-targeted SDT and conventional chemotherapy holds great clinical promise as an effective treatment modality with excellent biocompatibility that can improve MDR breast cancer patient outcomes.

The BET inhibitor JQ1 suppresses tumor survival by ABCB5-mediated autophagy in uveal melanoma

Uveal melanoma (UM), the most common adult ocular tumor, is aggressive and resistant to treatment, posing threat to patients' lives. The novel, effective therapies and the exploration of chemosensitizer for UM are imperative. The anticancer efficacy was evaluated with and without JQ1 treatment or ABCB5 gene silencing or overexpression. RNA sequencing identified downstream effectors in JQ1-treated cells. Integrated analysis of The Cancer Genome Atlas data (TCGA) and immunohistochemistry (IHC) revealed the oncogenic role of ABCB5. Functional analyses of JQ1 and defective ABCB5 were conducted using flow cytometry, transmission electron microscopy (TEM), IHC and western blot. The effects of JQ1 were validated in a heterotopic tumor model derived from OCM-1 cells. JQ1 inhibited cell proliferation, migration and invasion, induced cell cycle arrest and promoted apoptosis. JQ1 also suppressed the survival of UM in heterotopic tumor model. RNA sequencing indicated that JQ1 down-regulated the expressions of ABCB5 and autophagy-related genes, which was confirmed in vitro and in vivo by western blot. ABCB5, a marker associated with cancer stem cells and chemo-resistance, exhibited heightened expression in UM tissues, linked to immune infiltration. Notably, disrupting ABCB5 expression impeded UM cell proliferation and interfered with autophagy. Moreover, the overexpression of ABCB5 promoted cell proliferation, migration and invasion, and rescued autophagy related gene expression. Of note, JQ1 enhanced the sensitivity of OCM-1 cells to chemotherapy. Thus JQ1 inhibits UM survival via ABCB5-mediated autophagy and enhances chemo-sensitivity, suggesting potential for BET-based approaches in UM clinical management.

Targeting Mitochondrial Cholesterol Efflux via TCF21/ABCA10 Pathway to Enhance Cisplatin Efficacy in Ovarian Cancer.

Cisplatin (DDP) resistance is one of the causes of treatment failure for ovarian cancer (OV). Mitochondrial cholesterol level was reported to be associated with OV chemoresistance. We found that ABCA10, a potential cholesterol transport protein, was highly expressed in ovarian tissues and downregulated in OV tissues. Our study aimed to explore TCF21/ABCA10 axis resistance to DDP therapy in ovarian cancer based on regulating mitochondrial cholesterol efflux. Thirty epithelial ovarian cancer tumors and thirty ovarian tissues from non-cancer patients were collected. Western blot and RT-qPCR were used to measure ABCA10 and TCF21 expression levels in these tissues, as well as in a human ovarian epithelial cell line (IOSE-80), OV cells (A2780 and SKOV3), and DDP-resistant OV cell lines (A2780/DDP and SKOV3/DDP). IOSE-80 cells were also infected with ABCA10 knockdown lentivirus to identify the most effective ABCA10 knockdown plasmid. Lentiviral infection was used to create ABCA10 knockdown, ABCA10 overexpression, and TCF21 overexpression anti-DDP OV cell lines. Cell proliferation was detected by CCK-8 and EDU staining, flow cytometry for apoptosis, MTT for metabolic activity, calcium-induced Cytochrome C release, and mitochondrial matrix swelling for mitochondrial function and Oil Red O staining for lipid accumulation. Cholesterol metabolism was evaluated by measuring mitochondrial cholesterol and cholesterol efflux. Protein concentration was determined using the BCA method. A dual-luciferase reporter assay confirmed TCF21's interaction with ABCA10. ChIP also verified this interaction. The mRNA level (P < 0.01) and protein level (P < 0.001) of ABCA10 were downregulated in cancer tissues of OV patients relative to normal ovarian tissues. Relative to human ovarian epithelial cells, ABCA10 expression was significantly downregulated in OV cells (P < 0.01) and even more significantly downregulated in DDP-resistant OV cells (P < 0.001). Compared to the group treated solely with DDP, the overexpression of ABCA10 significantly inhibited the proliferation of DDP-resistant OV cells (P < 0.01), markedly reduced the staining intensity of EDU in these cells (P < 0.05), and substantially accelerated apoptosis in DDP-resistant OV cells (P < 0.01).Overexpression of ABCA10 further accelerated Cytochrome C expression and mitochondrial matrix swelling in DDP-resistant OV cells compared to the DDP-alone group (P < 0.01). The addition of cholesterol reversed the decrease in lipid accumulation, the decrease in mitochondrial cholesterol levels (P < 0.05), and the increase in cholesterol efflux (P < 0.01) in DDP-resistant OV cells caused by overexpression of ABCA10. The transcription factor TCF21 was bound to the promoter of ABCA10. Overexpression of TCF21 significantly increased ABCA10 expression in DDP-resistant OV cells (P < 0.01) and increased cytochrome C expression in A2780/DDP (P < 0.05) and SKOV3/DDP (P < 0.01) cells, with accelerated mitochondrial matrix swelling in A2780/DDP (P < 0.01) and SKOV3/DDP (P < 0.001) cells, while knockdown of ABCA10 reversed these effects. Our study found that TCF21 boosts ABCA10 expression, which in turn reduces DDP resistance in OV cells by enhancing mitochondrial cholesterol efflux. This mechanism increases the sensitivity of DDP-resistant OV cells to DDP. Our findings will provide new therapeutic targets for the treatment of ovarian cancer.

Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation.

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

Intracellular Magnetic Hyperthermia Sensitizes Sorafenib to Orthotopic Hepatocellular Carcinoma Via Amplified Ferroptosis.

Sorafenib (SRF) is recognized as the primary treatment for hepatocellular carcinoma (HCC), yet the emergence of SRF resistance in many HCC patients results in unfavorable outcomes. Enhancing the efficacy of SRF in HCC remains a significant challenge. SRF works in inducing ferroptosis, a form of cell death, in cancer cells through the inhibition of glutathione peroxidase 4 (GPX4). The effectiveness of this process is limited by the low levels of cellular iron and reactive oxygen species (ROS). A promising approach to circumvent this limitation is the use of intracellular magnetic hyperthermia (MH) mediated by magnetic iron oxide nanomaterials (MIONs). When MIONs are subjected to an alternating magnetic field (AMF), they heat up, enhancing the Fenton reaction, which in turn significantly increases the production of ROS within cells. In this study, we explore the capability of MH facilitated by high-performance ferrimagnetic vortex-domain iron oxide nanoring (FVIO) to enhance the effectiveness of SRF treatment in HCC. The increased iron uptake facilitated by FVIO significantly enhances the sensitivity of HCC cells to SRF-induced ferroptosis. Moreover, the nanoheat generated by FVIO in response to an AMF further elevates ROS levels and stimulates lipid hydroperoxide (LPO) production and GPX4 inactivation, thereby intensifying ferroptosis. Both in vitro and in vivo animal studies demonstrate that combining FVIO-mediated MH with SRF significantly reduces cell viability and inhibits tumor growth, primarily through enhanced ferroptosis, with minimal side effects. The effectiveness of this combination therapy is affected by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The combination treatment of FVIO-mediated MH and SRF offers a strategy for HCC treatment by promoting accelerated ferroptosis, presenting a different perspective for the development of ferroptosis-based anticancer therapies.

SiRNA-based strategies to combat drug resistance in gastric cancer.

Chemotherapy is a key treatment option for gastric cancer, but over 50% of patients develop either inherent or acquired resistance to these drugs, resulting in a 5-year survival rate of only about 20%. The primary treatment for advanced gastric cancer typically involves chemotherapy based on platinum or fluorouracil. Several factors can contribute to platinum resistance, including decreased drug uptake, increased drug efflux or metabolism, enhanced DNA repair, activation of pro-survival pathways, and inhibition of pro-apoptotic pathways. In recent years, there has been significant progress in biology aimed at finding innovative and more effective methods to overcome chemotherapy resistance. Small interfering RNAs (siRNAs) have emerged as a significant advancement in gene expression regulation, showing promise in enhancing the sensitivity of gastric cancer cells to chemotherapy drugs. However, siRNA therapies still face major challenges, particularly in terms of stability and efficient delivery in vivo. This article discusses the advances in siRNA therapy and its potential role in overcoming resistance to chemotherapeutic drugs such as cisplatin, 5-FU, doxorubicin, and paclitaxel in the treatment of gastric cancer.

Ribosomal S6 kinase (RSK) plays a critical role in DNA damage response via the phosphorylation of histone lysine demethylase KDM4B

BackgroundEpigenetic dysregulation affecting oncogenic transcription and DNA damage response is a hallmark of cancer. The histone demethylase KDM4B, a factor regulating these processes, plays important roles in estrogen receptor-mediated transcription and DNA repair in breast cancer. However, how oncogenic phospho-signal transduction affects epigenetic regulation is not fully understood. Here we found that KDM4B phosphorylation by ribosomal S6 kinase (RSK), a downstream effector of the Ras/MAPK pathway, is critical for the function of KDM4B in response to DNA damage.MethodsKDM4B-knockout breast cancer cell lines were generated via CRISPR/Cas9-mediated gene editing. Re-expression of wild-type or phospho-site mutated KDM4B in knockout cells was performed by lentivirus-mediated gene transfer. Gene knockdown was achieved by RNA interference. DNA double-strand breaks (DSBs) were induced by ionizing radiation or laser-microirradiation. Protein accumulation at DSB sites was analyzed by immunofluorescence. KDM4B phosphorylation by RSK was assessed by in vitro and in vivo kinase assays. Gene and protein expression levels were analyzed by RT‒PCR and western blotting. The sensitivity of cells to ionizing radiation was examined by a clonogenic survival assay.ResultsRSK phosphorylated KDM4B at Ser666, and inhibition of the phosphorylation by RSK depletion or RSK inhibitors abrogated KDM4B accumulation at the sites of DNA double-strand breaks (DSBs). DSB repair was significantly delayed in KDM4B-knockout cells or cells treated with RSK inhibitors. The replacement of endogenous KDM4B with the phosphomimetic mutant S666D restored KDM4B accumulation and DSB repair that had been inhibited by RSK inhibitors, suggesting a critical role for RSK at the specific serine residue of KDM4B in the effect of RSK inhibitors on DSB repair. As a consequence of these aberrant responses, inhibition of KDM4B phosphorylation increased the sensitivity of the cells to ionizing radiation.ConclusionsOverall, the present study uncovered a novel function of RSK on the DNA damage response, which provides an additional role of its inhibitor in cancer therapy.

Angelic acid triggers ferroptosis in colorectal cancer cells via targeting and impairing NRF2 protein stability.

Ferroptosis is a unique programmed cell death driven by iron-dependent phospholipid peroxidation. Tumor cells that escape from the conventional therapies appear more sensitive to ferroptosis. Therefore, it is extremely urgent to find safe and efficient active ingredients that induce ferroptosis in tumor cells. Herein, we identified that angelic acid, as a potent anti-tumor active ingredient in Angelica sinensis, profoundly sensitizes CRC cells to ferroptosis via a natural compound library screen. We revealed that angelic acid treatment is sufficient to predispose CRC cells to ferroptosis phenotype, evidenced by malondialdehyde (MDA) accumulation, lipid peroxidation, and upregulation of ferroptosis-associated markers CHAC1 and PTGS2, which is abolished by ferroptosis inhibitor Fer-1. Moreover, the results of network pharmacology showed that NRF2 is critical for angelic acid-mediated CRC cell ferroptosis. Mechanistically, angelic acid exerted its ferroptosis induction via directly binding and facilitating the degradation of NRF2. In addition, the syngeneic mouse models revealed that angelic acid boosts CRC cell sensitivity to ferroptosis inducer sulfasalazine with essentially no toxicity in vivo. Collectively, our findings highlighted a previously unrecognized anti-tumor mechanism of angelic acid and represented an appealing therapeutic strategy for CRC treatment.

LncRNA MAGI2-AS3 enhances cisplatin sensitivity of non-small cell lung cancer cells by regulating the miR-1269a/PTEN/AKT pathway

To investigate the mechanism mediating the regulatory effect of lncRNA MAGI2-AS3 on cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). MAGI2-AS3 and miR-1269a expression levels were detected by qRT-PCR in DDP-sensitive lung cancer cell lines (A549 and H1299) and their resistant counterparts (A549/DDP and H1299/DDP). In A549 and H1299 cells with MAGI2-AS3 silencing and A549/DDP and H1299/DDP cells overexpressing MAGI2-AS3, the effects of 20 μmol/L DDP on cell viability and apoptosis were examined with CCK-8 assay, colony formation assay, flow cytometry and Western blotting, and the changes in epithelial-mesenchymal transition (EMT) were assessed with wound healing and Transwell assays. The interaction between MAGI2-AS3, miR-1269a and PTEN was predicted using GEPIA, StarBase and miRDB and verified with luciferase reporter gene assay and radioimmunoprecipitation (RIP) assay. A miR-1269a mimic and pcDNA3.1-PTEN plasmid were used to perform the rescue assay. MAGI2-AS3 expression was significantly downregulated in lung cancer tissues (P < 0.05) in association with a poor prognosis (P < 0.05). In the two DDP-resistant lung cancer cell lines, MAGI2-AS3 expression was significantly lowered as compared with the sensitive cells. Silencing MAGI2-AS3 significantly enhanced cell viability and promoted EMT of A549 and H1299 cells irrespective of DDP treatment, and also decreased DDP-induced apoptosis of the cells. In A549/DDP and H1299/DDP cells, MAGI2-AS3 overexpression strongly repressed cell viability and EMT irrespective of DDP treatment and promoted DDP-induced cell apoptosis. Luciferase reporter gene and RIP assays confirmed the binding of MAGI2-AS3 with miR-1269a and the binding of miR-1269a with 3 '-UTR domain of PTEN. The rescue assay demonstrated that MAGI2-AS3 acted as a sponge for miR-1269a to promote PTEN expression and downregulate AKT phosphorylation, thus inhibiting EMT and promoting DDP-induced apoptosis of A549/DDP cells. MAGI2-AS3 enhances DDP sensitivity of NSCLC by targeted regulation of the miR-1269a/PTEN/AKT signaling axis.

In vivo delivery of PBAE/ZIF-8 enhances the sensitivity of colorectal cancer to doxorubicin through sh-LncRNA ASB16-AS1.

The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.

Protein kinase D1 mitigation against etoposide induced DNA damage in prostate cancer is associated with increased α-Catenin.

The E-cadherin, α- and β-Catenin interaction at the cell adherens junction plays a key role in cell adhesion; alteration in the expression and function of these genes are associated with disease progression in several solid tumors including prostate cancer. The membranous β-Catenin is dynamically linked to the cellular cytoskeleton through interaction with α-Catenin at amino acid positions threonine 120 (T120) to 151 of β-Catenin. Nuclear presence of α-Catenin modulates the sensitivity of cells to DNA damage. The objective of this study is to determine the role of α-Catenin and protein kinase D1 (PrKD1) in DNA damage response. Prostate cancer cells; LNCaP, LNCaP (Sh-PrKD1; silenced PrKD1), C4-2 and C4-2 PrKD1 were used for various sets of experiments to determine the role of DNA damage in PrKD1 overexpression and silencing cells. These cells were treated with compound-10 (100 nM) and Etoposide (30 µM), total cell lysates, cytosolic and nuclear fractions were prepared to observe various protein expressions. We performed single cell gel electrophoresis (COMET assay) to determine the etoposide induce DNA damage in C4-2 and C4-2 PrKD1 cells. The animal experiments were carried out to determine the tolerability of compound-10 by mice and generate preliminary data on efficacy of compound-10 in modulating the α-Catenin and PrKD1 expressions in inhibiting tumor progression. PrKD1, a novel serine threonine kinase, phosphorylates β-Catenin T120. In silico analysis, confirmed that T120 phosphorylation alters β- to α-Catenin binding. Forced expression of PrKD1 in prostate cancer cells increased β- and α-Catenin protein levels associated with reduced etoposide induced DNA damage. Downregulation of α-Catenin abrogates the PrKD1 mitigation of DNA damage. The in vitro results were corroborated in vivo using mouse prostate cancer patient derived xenograft model by inhibition of PrKD1 kinase activity with compound-10, a selective PrKD inhibitor, demonstrating decreased total β- and α-Catenin protein levels, and β-Catenin T120 phosphorylation. Alteration in DNA damage response pathways play major role in prostate cancer progression. The study identifies a novel mechanism of α-Catenin dependent DNA damage mitigation role for PrKD1 in prostate cancer.

Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.

Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.

Scaffolds functionalized with matrix metalloproteinase-responsive release of miRNA for synergistic magnetic hyperthermia and sensitizing chemotherapy of drug-tolerant breast cancer

Combining hyperthermia and chemotherapy for maximum anticancer efficacy remains a challenge because drug-tolerant cancer cells often evade this synergistic treatment due to drug resistance and asynchronous drug release. In this study, multifunctional scaffolds were designed to efficiently treat drug-tolerant breast cancer by improving the sensitization of breast cancer cells and synchronizing anticancer drug release with magnetic hyperthermia. The scaffolds contained microRNA-encapsulated matrix metalloproteinase-cleavable liposomes, doxorubicin-encapsulated thermoresponsive liposomes and Fe3O4 nanoparticles. The scaffolds could release microRNA specifically to improve the sensitization of breast cancer cells to anticancer drugs. The scaffolds also showed excellent hyperthermia effects under alternating magnetic field irradiation. Moreover, doxorubicin release was synchronized with magnetic hyperthermia. In vitro and in vivo studies demonstrated that the scaffolds effectively reduced drug resistance and eliminated doxorubicin-tolerant MDA-MB-231 cells through the synergistic effect of magnetic hyperthermia and sensitizing chemotherapy. Additionally, the scaffolds could support the proliferation and adipogenic differentiation of stem cells for adipose tissue regeneration after killing cancer cells at a late therapeutic stage. These composite scaffolds offer an innovative strategy for treating breast cancer, with synergistic anticancer effects and regenerative functions.