Inhibit Cancer Progression Research Articles

Low Expression of FAM96B is Associated with Poor Prognosis in Hepatocellular Carcinoma.

Recently, studies on FAM96B functions mainly focused on its role in maintaining the normal physiological function of cells. However, the clinical implications of FAM96B in hepatocellular carcinoma (HCC) are still unclear. FAM96B mRNA expression was detected in human HCC tissues and the matched nontumorous tissues by quantitative real-time reverse transcription (qRT-PCR) and then validated in The Cancer Genome Atlas (TCGA) database. Immunohistochemistry assay (IHC) was performed on all 137 cases of HCC samples to examine the protein level of FAM96B. Subsequently, the associations between FAM96B expression and clinicopathological parameters and prognosis were further analyzed. The mRNA level of FAM96B was found to be significantly lower in HCC tissues compared to non-tumorous tissues, as observed in both the local hospital and TCGA database.Immunohistochemistry assay analysis revealed a decrease in FAM96B expression in 78 out of 137 cases, which was significantly associated with larger tumor size, higher Barcelona clinic liver cancer or Child stage, and early distant metastasis. Patients with low FAM96B levels tended to have an unfavorable disease-free and overall survival. Moreover, FAM96B was identified as an independent predictor of patient prognosis in both univariate and multivariate survival analyses. Mechanistically, FAM96B was found to inhibit cancer progression by inducing apoptosis in liver cancer cells and inhibiting their growth. Our findings provide the first evidence suggesting the involvement of FAM96B in the progression of HCC. Additionally, FAM96B could potentially serve as a marker for tumor recurrence and prognosis in HCC patients.

Unlocking the epigenetic code: new insights into triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive and clinically challenging subtype of breast cancer, lacking the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. The absence of these receptors limits therapeutic options necessitating the exploration of novel treatment strategies. Epigenetic modifications, which include DNA methylation, histone modifications, and microRNA (miRNA) regulation, play a pivotal role in TNBC pathogenesis and represent promising therapeutic targets. This review delves into the therapeutic potential of epigenetic interventions in TNBC, with a focus on DNA methylation, histone modifications, and miRNA therapeutics. We examine the role of DNA methylation in gene silencing within TNBC and the development of DNA methylation inhibitors designed to reactivate silenced tumor suppressor genes. Histone modifications, through histone deacetylation and acetylation in particular, are critical in regulating gene expression. We explore the efficacy of histone deacetylase inhibitors (HDACi), which have shown promise in reversing aberrant histone deacetylation patterns, thereby restoring normal gene function, and suppressing tumor growth. Furthermore, the review highlights the dual role of miRNAs in TNBC as both oncogenes and tumor suppressors and discusses the therapeutic potential of miRNA mimics and inhibitors in modulating these regulatory molecules to inhibit cancer progression. By integrating these epigenetic therapies, we propose a multifaceted approach to target the underlying epigenetic mechanisms that drive TNBC progression. The synergistic use of DNA methylation inhibitors, HDACi, and the miRNA-based therapies offers a promising avenue for personalized treatment strategies, aiming to enhance the clinical outcome for patients with TNBC.

Extrajunctional CLDN10 cooperates with LAT1 and accelerates clear cell renal cell carcinoma progression

Background & aimsIn addition to their adhesive properties, cell adhesion molecules such as claudins (CLDNs) exhibit signaling ability to organize diverse cellular events. Although the CLDN-adhesion signaling stimulates or inhibits cancer progression, the underlying mechanism remains poorly established. Here, we verified whether and how CLDN10 promotes intracellular signals and malignant phenotypes in clear cell renal cell carcinoma (ccRCC).MethodsWe developed a novel monoclonal antibody that specifically recognizes CLDN10. By immunohistochemistry using this antibody, the clinicopathological significance of aberrant CLDN10 expression in 165 ccRCC patients was determined. We next generated the ccRCC cells (786-O, ACHN, and OS-RC-2) expressing CLDN10, and compared their phenotypes with those of control cells. Immunoprecipitation-mass spectrometry was used to identify a CLDN10-interacting protein, followed by evaluation of its association with CLDN10 and loss-of-functions in ccRCC cells.ResultsHigh CLDN10 expression predicted poor outcome in ccRCC patients and represented an independent prognostic marker for cancer-specific survival. Cell surface CLDN10 promoted cell viability, proliferation, and migration of ccRCC cells, as well as their tumor growth. CLDN10 also activated mTOR signaling and expression of downstream targets, including MYC target genes. Notably, we found that CLDN10 forms a complex with an amino acid transporter, LAT1, and that CLDN10–LAT1 signaling facilitates malignant phenotypes in ccRCC cells. Structural prediction and immunoprecipitation analysis results strongly suggest an interaction between CLDN10-TM1 (transmembrane domain 1) and LAT1-TM4.ConclusionsWe conclude that CLDN10–LAT1 signaling drives ccRCC progression. Taken together with our previous findings on CLDN–Src-family kinases signaling, CLDNs propagate distinct intracellular signals depending on their association with different binding partners.

Combination Effect of Radiotherapy and Targeted Therapy with NK Cell-Based Immunotherapy in head and Neck Squamous Cell Carcinoma

ABSTRACT Background Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and current treatments are limited by high toxicity and low survival rates, highlighting the need for new therapeutic approaches. Natural killer (NK) cells can identify and eliminate cancer cells without prior antigen exposure. Radiotherapy directly targets tumors and increases activating ligands on tumor cells, promoting NK cell interactions. Cetuximab, an EGFR-targeting antibody, enhances NK cell cytotoxicity. Additionally, anti-PD-1 antibodies may further boost NK cell function by blocking inhibitory signals. The study aimed to enhance HNSCC treatment efficacy by combining radiotherapy and targeted therapy with expanded NK cells. Methods NK cells were isolated, activated, and expanded from healthy donors. The FaDu and SCC-47 cell lines were inoculated into NOD/SCID mice. The mice were treated with PD-1 inhibitors, cetuximab, and radiation, followed by intravenous injection of NK cells. Results Radiation increased ligands that regulate NK cell sensitivity. The combination of cetuximab, radiotherapy, and expanded NK cells significantly suppressed cancer progression and improved survival rates. However, adding anti-PD-1 antibodies did not further enhance outcomes. Conclusion This study suggests that a multimodal approach combining cetuximab, radiotherapy, and NK cells can significantly improve HNSCC therapy efficacy, offering a novel and promising treatment strategy.

Carcinoma-Associated Fibroblasts Accelerate Growth and Invasiveness of Breast Cancer Cells in 3D Long-Term Breast Cancer Models.

Background/Objectives: Carcinoma-associated fibroblasts (CAFs), a prominent cell type in the tumor microenvironment (TME), significantly contributes to cancer progression through interactions with cancer cells and other TME components. Consequently, targeting signaling pathways driven by CAFs has potential to yield new therapeutic approaches to inhibit cancer progression. However, the mechanisms underlying their long-term interactions with cancer cells in vivo remains poorly understood. Methods: To address this, we developed a three-dimensional (3D) parallel coculture model of human triple-negative breast cancer (TNBC) cells and CAFs using our innovative TAME devices. This model allowed for the analysis of TNBC paracrine interactions via their secretome over extended culture periods (at least 70 days). Results: Using TNBC cell lines (MDA-MB-231, MCF10.DCIS, and HCC70), we found that TNBC spheroids in 3D parallel cocultures with CAFs exhibited more pronounced invasive finger-like outgrowths than those in cocultures of TNBC cells and normal fibroblasts (NFs) over a period of 50-70 days. We also established that the CAF-derived secretome affects TNBC migration towards the CAF secretome region. Additionally, we observed a preferential migration of CAFs, but not NFs, toward TNBC spheroids. Conclusions: Overall, our results suggest that paracrine interactions between TNBC cells and CAFs enhance TNBC invasive phenotypes and promote reciprocal migration.

Targeting G-quadruplex by TMPyP4 for inhibition of colorectal cancer through cell cycle arrest and boosting anti-tumor immunity

G-quadruplex (G4) is a noncanonical DNA secondary structure known to induce DNA damage and regulate the expression of immune-related genes. We aim to exploit the G4 folding as a treatment strategy to trigger anti-tumor immune response. In this study, we observe that the abundant genomic G4 in epithelial cells coexists with increased infiltration of CD8+ T cells in colorectal cancer tissue. Furthermore, our data substantiate the inhibitory effect of the G4 ligand TMPyP4 on cancer progression while concurrently stimulating anti-tumor immunity. Mechanistically, TMPyP4 impedes cancer cell proliferation and induces G2/M cell cycle arrest. Additionally, in vivo experiments demonstrate that TMPyP4 enhances the anti-tumor immune response by triggering DNA damage and activating the cGAS-STING pathway, which fosters CD8+ T cell activation and dendritic cell maturation. Importantly, the combined treatment of TMPyP4 and anti-PD1 exhibits a synergistic therapeutic effect on colorectal cancer. In summary, our findings underscore the potential of the G4 ligand TMPyP4 as a dual strategy to target colorectal cancer: inhibiting cancer progression and augmenting anti-tumor immunity through the activation of cGAS-STING pathway.

Exploring the dual role of endoplasmic reticulum stress in urological cancers: Implications for tumor progression and cell death interactions.

The endoplasmic reticulum (ER) is crucial for maintaining calcium balance, lipid biosynthesis, and protein folding. Disruptions in ER homeostasis, often due to the accumulation of misfolded or unfolded proteins, lead to ER stress, which plays a significant role in various diseases, especially cancer. Urological cancers, which account for high male mortality worldwide, pose a persistent challenge due to their incurability and tendency to develop drug resistance. Among the numerous dysregulated biological mechanisms, ER stress is a key factor in the progression and treatment response of these cancers. This review highlights the dual role of aberrant ER stress activation in urologic cancers, affecting both tumor growth and therapeutic outcomes. While ER stress can support tumor growth through pro-survival autophagy, it primarily inhibits cancer progression via apoptosis and pro-death autophagy. Interestingly, ER stress can paradoxically aid cancer progression through mechanisms such as exosome-mediated immune evasion. Additionally, the review examines how pharmacological interventions, particularly with phytochemicals, can stimulate ER stress-mediated tumor suppression. Key regulators, including PERK, IRE1α, and ATF6, are discussed for their roles in upregulating CHOP levels and triggering apoptosis. In conclusion, a deeper understanding of ER stress in urological cancers not only clarifies the complex interactions between cellular stress and cancer progression but also provides new opportunities for innovative therapeutic strategies.

Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma

ObjectiveResveratrol (Res) is a promising anticancer drug against hepatocellular carcinoma (HCC), but whether its anti-HCC effects implicate mitophagy remains unclear. Therefore, we aimed to explore the specific role of Res in mitophagy and the related mechanisms during the treatment of HCC. MethodsHepG2 cells and tumor-grafted nude mice were used to investigate the effects of low-, middle- and high-dose of Res on HCC progression and mitophagy in vitro and in vivo, respectively. A series of approaches including cell counting kit-8, flow cytometry, wound healing and transwell assays were used to evaluate tumor cell functions. Transmission electron microscopy, immunofluorescence and Western blotting analysis were used to assess mitophagy. Mitochondrial oxygen consumption rate, reactive oxygen species and membrane potential were used to reflect mitochondrial function. After disrupting the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-143-3p, and ribonucleoside reductase M2 (RRM2), the effects of the MALAT1/miR-143-3p/RRM2 axis on cell function and mitophagy under Res treatment were explored in vitro. Additionally, dual-luciferase reporter and chromatin immunoprecipitation were used to confirm interactions between target genes. ResultsRes significantly inhibited the proliferation and promoted apoptosis of HCC cells in vitro, while significantly suppressing tumor growth in a dose-dependent manner and inducing mitophagy and mitochondrial dysfunction in vivo. Interestingly, MALAT1 was highly expressed in HCC cells and its knockdown upregulated miR-143-3p expression in HCC cells, which subsequently inhibited RRM2 expression. Furthermore, in nude mice grafted with HCC tumors and treated with Res, the expression of MALAT1, miR-143-3p and RRM2 were altered significantly. In vitro data further supported the targeted binding relationships between MALAT1 and miR-143-3p and between miR-143-3p and RRM2. Therefore, a series of cell-based experiments were carried out to study the mechanism of the MALAT1/miR-143-3p/RRM2 axis involved in mitophagy and HCC; these experiments revealed that MALAT1 knockdown, miR-143-3p mimic and RRM silencing potentiated the antitumor effects of Res and its activation of mitophagy. ConclusionRes facilitated mitophagy in HCC and exerted anti-cancer effects by targeting the MALAT1/miR-143-3p/RRM2 axis.

Targeting NUCKS1 with a fragment of tRNAAsn(GUU) of Chinese yew for the treatment of colorectal cancer

Despite the discovery of numerous oncogenes in colorectal cancer (CRC), the development of associated drugs is limited, posing a significant challenge for CRC treatment. Identification of novel druggable targets is therefore crucial for the therapeutic development of CRC. Here, we report the first investigation on therapeutics targeting the potent oncogene NUCKS1 to suppress cancer progression. NUCKS1-orientated bioinformatics screening of NUCKS1 inhibitors from our library of tRNA fragments originated from medicinal plants identified tRF-T36, a 5' tRNA fragment of tRNAAsn(GUU) of Chinese yew (Taxus chinensis), exhibiting stronger inhibitory effects than taxol against CRC progression. Mechanistically, tRF-T36 binds directly to the 3' UTR of NUCKS1 mRNA to downregulate its expressions via RNAi pathway. High-throughput RNA sequencing indicated that the downregulated NUCKS1 induced by tRF-T36 further inhibits PI3K/Akt pathway, as verified by the significantly efficacy decrease of tRF-T36 mimic in co-treatment with 740Y-P, an agonist of PI3K/Akt pathway. Collectively, our findings emphasize the importance of NUCKS1 as a promising druggable target for CRC. Furthermore, the present study provides the first siRNA sequence, tRF-T36 mimic, as small RNA drug candidate, thereby shedding light on CRC therapeutics.

Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression.

Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a critical regulator for the homeostasis between ribosome biogenesis and p53 activation. BRIX1 facilitated the processing of pre-rRNA by supporting the formation of the PeBoW complex. In addition, BRIX1 prevented p53 activation in response to nucleolar stress by impairing the interactions between MDM2 and the ribosomal proteins, RPL5, and RPL11, thereby triggering the resistance of cancer cells to chemotherapy. Conversely, depletion of BRIX1 induced nucleolar stress, which in turn activated p53 through RPL5 and RPL11, consequently inhibiting the growth of tumors. Moreover, engineered exosomes are developed, which are surface-decorated with iRGD, a tumor-homing peptide, and loaded with siRNAs specific to BRIX1, for the treatment of cancer. iRGD-Exo-siBRIX1 significantly suppressed the growth of colorectal cancer and enhanced the efficacy of 5-FU chemotherapy in vivo. Overall, the study uncovers that BRIX1 functions as an oncoprotein to promote rRNA synthesis and dampen p53 activity, and also implies that targeted inhibition of BRIX1 via engineered exosomes can be a potent approach for cancer therapy.

LSD1 Demethylates and Destabilizes Autophagy Protein LC3B in Ovarian Cancer.

Autophagy is a complex cellular process that can either promote or inhibit cancer progression and development, depending on the context and molecular regulation involved. This study investigates how LSD1 regulates autophagy in ovarian cancer by interacting with the autophagy protein LC3B. Utilizing the bioinformatic analysis of TCGA, CPTAC, and GEO datasets, as well as immunohistochemistry in ovarian cancer patients, we explored the expression association between LSD1 and LC3B. Molecular mechanisms were further analyzed using Western blotting, immunoprecipitation, and GST pull-down assays. Our findings reveal that LSD1 binds to LC3B via its SWIRM domain, and high levels of LSD1 are closely associated with aggressive ovarian cancer and poor patient outcomes. Mechanistically, LSD1 demethylates LC3B, leading to decreased LC3B stability. The observed inverse correlation between LSD1 expression and LC3B protein levels in clinical samples underscores the need for further investigation to elucidate how reduced LC3B protein levels induced by LSD1 demethylation may contribute to ovarian cancer.

SNHG15 Mediates MTSS1 Gene Expression via Interacting with the Gene Promoter and Regulating Transcription Pausing.

Metastasis suppressor 1 (MTSS1) has been reported to play important roles in suppressing cancer progression. In this study, we investigated the underlying mechanism that regulates MTSS1 expression. We showed that in breast cancer cells, lncRNA-SNHG15-induced cell invasion and proliferation was accompanied with the decreased expression of MTSS1 mRNA. Further study revealed that SNHG15 mediated MTSS1 repression through blocking its promoter activity. Mechanistically, SNHG15 complexes with DDX5 and RTF1 and interacts with the core promoter of the MTSS1 gene to interfere with RNA-Pol-II-directed transcriptional initiation. Association with DDX5 stabilizes SNHG15 while binding to RTF1 allows SNHG15 to carry RTF1 to the core promoter, where RTF1 forms a complex with PNA pl II to enhance transcriptional pausing. Our findings revealed a molecular mechanism by which SNHG15 serves as a regulator to suppresses MTSS1 transcription via interaction with the gene core promoter.

Targeted Delivery of Celastrol by GA-Modified Liposomal Calcium Carbonate Nanoparticles to Enhance Antitumor Efficacy Against Breast Cancer.

Breast cancer, a leading health threat affecting millions worldwide, requires effective therapeutic interventions. Celastrol (CEL), despite its antitumor potential, is limited by poor solubility and stability. This study aimed to enhance CEL's efficacy by encapsulating it within glycyrrhizic acid (GA)-modified lipid calcium carbonate (LCC) nanoparticles for targeted breast cancer therapy. The 4T1 mouse breast cancer cells were used for the study. GA-LCC-CEL nanoparticles were prepared using a gas diffusion method and a thin-film dispersion method. GA-LCC-CEL were characterized using the zeta-potential, dynamic light scattering and transmission electron microscope (TEM). The in vitro release behavior of nanoparticles was assessed using the in vitro dialysis diffusion method. Cellular uptake was examined using flow cytometry and confocal microscopy. Intracellular ROS and Rhodamine 123 levels were observed under fluorescence microscopy. MTT and colony formation assays assessed cytotoxicity and proliferation, and apoptosis was analyzed by Annexin V-FITC/PI staining. Wound healing and transwell assays evaluated migration, and Western blotting confirmed protein expression changes related to apoptosis and migration. GA-LCC-CEL nanoparticles displayed a well-defined core-shell structure with a uniform size distribution. They showed enhanced anti-proliferative and pro-apoptotic effects against 4T1 cells and significantly reduced breast cancer cell invasion and migration. Additionally, GA-LCC-CEL modulated epithelial-mesenchymal transition (EMT) protein expression, downregulating Snail and ZEB1, and upregulating E-cadherin. GA-LCC-CEL nanoparticles represent a promising targeted drug delivery approach for breast cancer, enhancing CEL's antitumor efficacy and potentially inhibiting cancer progression by modulating EMT-related proteins.

Regular exercise suppresses steatosis-associated liver cancer development by degrading E2F1 and c-Myc via circadian gene upregulation.

Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis-associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non-exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c-Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c-Myc was transcriptionally unchanged but degraded at the post-translational level by exercise. Cry2, which is regulated by the Skp1-Cul1-FBXL3 (SCFFBXL3) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c-Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development.

Cancer Pathways Targeted by Berberine: Role of microRNAs.

Cancer is a complex and heterogeneous malignant disease. Due to its multifactorial nature, including progressive changes in genetic, epigenetic, transcript, and protein levels, conventional therapeutics fail to save cancer patients. Evidence indicates that dysregulation of microRNA (miRNA) expression plays a crucial role in tumorigenesis, metastasis, cell proliferation, differentiation, metabolism, and signaling pathways. Moreover, miRNAs can be used as diagnostic and prognostic markers and therapeutic targets in cancer. Berberine, a naturally occurring plant alkaloid, has a wide spectrum of biological activities in different types of cancers. Inhibition of cell proliferation, metastasis, migration, invasion, and angiogenesis, as well as induction of cell cycle arrest and apoptosis in cancer cells, is reported by berberine. Recent studies suggested that berberine regulates many oncogenic and tumor suppressor miRNAs implicated in different phases of cancer. This review discussed how berberine inhibits cancer growth and propagation and regulates miRNAs in cancer cells. And how berberine-mediated miRNA regulation changes the landscape of transcripts and proteins that promote or suppress cancer progression. Overall, the underlying molecular pathways altered by berberine and miRNA influencing the tumor pathophysiology will enhance our understanding to combat the malignancy.

MiR-149-3p targeting TMPRSS4 regulates the sensitivity to cisplatin to inhibit the progression of lung cancer.

Lung cancer cells tend to develop resistance to cisplatin (DDP) during continuous chemotherapy, making it crucial to improve DDP sensitivity to enhance therapeutic outcomes. The levels of miR-149-3p in lung tissues and cells, as well as the biological behaviors of lung cancer cells, were analyzed. H446/DDP and A549/DDP cell lines were established to investigate how miR-149-3p affects lung cancer cells' sensitivity to DDP. Bioinformatics analysis predicted transmembrane serine protease 4 (TMPRSS4) as a downstream target of miR-149-3p, which was subsequently confirmed. Western blot analysis was used to examine proteins related to migration, invasion, apoptosis, and TMPRSS4 expression. Additionally, a subcutaneous graft tumor model in nude mice was created to assess the impact of miR-149-3p on tumor growth. In lung cancer tissues and cells, miR-149-3p expression was reduced, while TMPRSS4 expression was elevated. Overexpression of miR-149-3p inhibited cancer progression, promoted apoptosis, and enhanced the chemosensitivity of lung cancer cells to DDP. Moreover, miR-149-3p negatively regulated TMPRSS4, reducing malignancy-associated characteristics of lung cancer cells and further improving their DDP sensitivity. In vivo, high miR-149-3p expression increased the chemosensitivity of cancer cells. In conclusion, miR-149-3p suppresses the aggressive progression of lung cancer by directly downregulating TMPRSS4 and enhances the responsiveness of lung cancer cells to DDP.

The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy.

Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy.

Excessive autophagy-inducing and highly penetrable biomineralized bacteria for multimodal imaging-guided and mild hyperthermia-enhanced immunogenic cell death

The tumor microenvironment, characterized by hypoxia, supports the efficacy of anaerobic bacteria like attenuated S. typhimurium in cancer therapies. These bacteria target and penetrate deep tumor regions, significantly reducing tumor size but often lead to tumor regrowth due to limited long-term efficacy. To enhance the therapeutic impact, a novel biohybrid system, S@UIL, has been developed by coating S. typhimurium with a zirconium-based nanoscale metal–organic framework (UiO-66-NH2) loaded with indocyanine green (ICG) and luteolin (LUT). This system maintains the bacteria’s tumor-targeting ability while increasing the penetration and therapeutic effectiveness through excessive autophagy and mild hyperthermia. In a subcutaneous colon cancer model, the integration of LUT and ICG promotes autophagic cell death and photothermal sensitization, leading to the release of damage-associated molecular patterns (DAMPs). These DAMPs activate immune responses through dendritic cells and T-cells, enhancing immunogenic cell death (ICD) and potentially reducing immune evasion by tumors. This single-administration approach also integrates multimodal imaging capabilities, providing a promising strategy for improved tumor ICD induction and cancer progression inhibition.

Targeting hypoxia-inducible factor 1 alpha augments synergistic effects of chemo/immunotherapy via modulating tumor microenvironment in a breast cancer mouse model

Introduction: The immunosuppressive context of the tumor microenvironment (TME) is a significant hurdle in breast cancer (BC) treatment. Combinational therapies targeting cancer core signaling pathways involved in the induction of TME immunosuppressive milieu have emerged as a potent strategy to overcome immunosuppression in TME and enhance patient therapeutic outcomes. This study presents compelling evidence that targeting hypoxia-inducible-factor-1 alpha (Hif-1α) alongside chemotherapy and immune-inducing factors leads to substantial anticancer effects through modulation of TME. Methods: Chitosan (Cs)/Hif-1alpha siRNA nano-complex was synthesized by siRNA adsorption methods. Nanoparticles were fully characterized using dynamic light scattering and scanning electron microscope. Cs/Hif-1α siRNA cytotoxicity was measured by MTT assay. The anticancer effects of the combinational therapy were assessed in BALB/c bearing 4T1 tumors. qPCR and western blotting were applied to assess the expression of some key genes and proteins involved in the induction of immunosuppression in TME. Results: Hif-1α siRNA was successfully loaded in chitosan nanoparticles. Hif-1α siRNA nanocomplexes significantly inhibited the expression of Hif-1α. Triple combination therapy (Paclitaxel (Ptx) + Imiquimod (Imq) + Cs/Hif-1α siRNA) inhibited tumor growth and downregulated cancer progression genes while upregulating cellular-immune-related cytokines. Mice without Cs/Hif-1α siRNA treatments revealed fewer cancer inhibitory effects and more TME immunosuppressive factors. These results suggest that the inhibition of Hif-1α effects synergize with Ptx and Imq to inhibit cancer progression more significantly than other combinational treatments. Conclusion: Combining Hif-1α siRNA with Ptx and Imq is promising as a multimodality treatment. It has the potential to attenuate TME inhibitory effects and significantly enhance the immune system's ability to combat tumor cell growth, offering an inspiration of hope in the fight against BC.

Mechanistic insights into the impact of WIN 55, 212-2, a synthetic cannabinoid, on adhesion molecules PECAM-1 and VE-cadherin in HeLa cells: implications on cancer processes

The endocannabinoid (eCB) system comprises endogenous ligands, cannabinoid receptors (CBRs), and their regulatory proteins; its alteration leads to many diseases including cancer. Thus, becomes a therapeutic target for synthetic cannabinoids aimed to control cancer cell proliferation, migration, adhesion, and invasion. However, little is known about adhesion molecules regulation through CBRs activation. The aim of this study was to evaluate the effects of a CB1/CB2 agonist, WIN-55, 212-2 (WIN), on the regulation of adhesion molecules platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial cadherin (VE-cadherin) in HeLa cells. CBRs expression was evaluated by immunofluorescence staining in HeLa cells and cell viability (thiazolyl blue tetrazolium bromide), cell adhesion (crystal violet), adhesion molecules expression and location (Western blot and immunofluorescence staining assays) were all assessed on cells treated with different WIN concentrations. Receptors CB1, CB2, and G-protein-coupled receptor 55 were expressed in HeLa cells. Additionally, biphasic effects were observed in their metabolic activity and adhesive properties: low WIN concentrations resulted in significant increases whereas, high ones decreased them compared to controls (p < 0.0001), demonstrating that WIN elicits opposite effects depending on the concentration and exposure time. PECAM-1 was detected in HeLa cell’s cytoplasm, membrane, and perinuclear region, whereas VE-cadherin had a nuclear distribution. There were no significant differences in PECAM-1 and VE-cadherin expression and location, suggesting that WIN does not modulate these proteins. These findings support the potential use of WIN due to its anticancer properties without dysregulating adhesion molecules. WIN possible contribution to inhibit cancer progression should be further investigated.