Promotes Cisplatin Resistance Research Articles

FOXA1 activates NOLC1 transcription through NOTCH pathway to promote cell stemness in lung adenocarcinoma.

Tumor cell stemness plays a pivotal role in generating functional heterogeneity within tumors and is implicated in essential processes such as drug resistance, metastasis, and cell proliferation. Therefore, creating novel tumor diagnostic techniques and therapeutic plans requires a knowledge of the possible processes that preserve the stem cell-like qualities of cancers. Bioinformatics analysis of NOLC1 expression in lung adenocarcinoma (LUAD) and prediction of its upstream transcription factors and their binding sites were completed. RT-qPCR detection of NOLC1 and FOXA1 expression, colony formation assay of cell proliferation, Transwell assay of cell invasion, sphere formation assay of cell stemness, western blot detection of CD133, OCT4, GLI1, NOTCH1 and Hes1 expression, CCK-8 assay of IC50 value of cisplatin, and ChIP and dual-luciferase reporter validation of binding relationship between NOLC1 and FOXA1 were done. NOLC1 expression was elevated in LUAD cells and tissues. Decreased NOLC1 expression inhibited the proliferation and invasive capacity of LUAD cells, prevented LUAD cells from becoming stem cells, and suppressed cisplatin resistance in the cells. Rescue tests demonstrated that NOLC1 activated the NOTCH pathway to increase the stemness of LUAD cells and promoted cisplatin resistance in LUAD cells. The activation of NOLC1 transcription by FOXA1 was validated by bioinformatics prediction and molecular verification, and the FOXA1/NOLC1 axis enhanced the stemness of LUAD cells. Activation of NOLC1 transcription by FOXA1 through NOTCH pathway promoted stemness of LUAD. FOXA1/NOLC1 axis is expected to become a new target for inhibiting stemness of LUAD cells.

Different Cytotoxic Effects of Cisplatin on Pancreatic Ductal Adenocarcinoma Cell Lines

This study examined the response to cisplatin in BxPC-3, Mia-Paca-2, PANC-1, and YAPC pancreatic cancer lines with different genotypic and phenotypic characteristics, and the mechanisms associated with their resistance. BxPC-3 and MIA-PaCa-2 cell lines were the most sensitive to cisplatin, while YAPC and PANC-1 were more resistant. Consistently, in cisplatin-treated BxPC-3 cells, the cleavage patterns of pro-caspase-9, -7, -3, and PARP-1 demonstrated that they were more sensitive than YAPC cells. The autophagic pathway, promoting cisplatin resistance, was active in BxPC-3 cells, as demonstrated by the time-dependent conversion of LC3-I to LC3-II, whereas it was not activated in YAPC cells. In cisplatin-treated BxPC-3 cells, Bcl-2 decreased, while Beclin-1, Atg-3, and Atg-5 increased along with JNK1/2 phosphorylation. Basal levels of phosphorylated ERK1/2 in each cell line were positively correlated with cisplatin IC50 values, and cisplatin caused the activation of ERK1/2 in BxPC-3 and YAPC cells. Furthermore, ERK1/2 pharmacological inactivation increased cisplatin lethality in both BxPC-3 and YAPC cells, suggesting that p-ERK1/2 may be related to cisplatin resistance of PDAC cells. Different mechanisms and strategies are generally required to acquire drug resistance. Here, we partially explain the other response to cisplatin of BxPC-3 and YAPC cell lines by relating it to the role of ERK pathway.

USP5-dependent HDAC1 promotes cisplatin resistance and the malignant progression of non-small cell lung cancer by regulating RILP acetylation levels.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with cisplatin (DDP) resistance being a significant challenge in its treatment. Histone deacetylase 1 (HDAC1) has been implicated in the regulation of NSCLC progression; however, its role in the resistance of NSCLC to DDP remains unclear. The mRNA levels of HDAC1, ubiquitin specific peptidase 5 (USP5), and Rab interacting lysosomal protein (RILP) were analyzed by quantitative real-time polymerase chain reaction. The protein expression of HDAC1, multidrug resistance protein 1 (MRP1) and RILP was detected by western blotting assay or immunohistochemistry assay. The IC50 value of DDP was determined using a cell counting kit-8 assay, while cell proliferation, apoptosis, and invasion were assessed using 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, and trans well invasion assay, respectively. Cancer stem-like cell properties were analyzed by a sphere formation assay. The interaction between USP5 andHDAC1 was investigated using MG132 assay and co-immunoprecipitation (Co-IP).RILP acetylation was analyzed by a Co-IP assay. A xenograft mouse model assay was employed to study the in vivo effects of HDAC1 silencing on DDP sensitivity. HDAC1 expression was upregulated in DDP-resistant NSCLC tissues and cells. Silencing HDAC1 enhanced the sensitivity of NSCLC cells to DDP, inhibited cell proliferation, invasion, and the formation of microspheres and induced cell apoptosis. USP5 was found to deubiquitinate and stabilize HDAC1 in DDP-resistant NSCLC cells. Moreover, HDAC1 overexpression reversed the effects induced by USP5 silencing. HDAC1 also sensitized Rab-interacting lysosomal protein (RILP) acetylation in DDP-resistant NSCLC cells, and RILP upregulation counteracted the effects of HDAC1 overexpression in DDP-resistant NSCLC cells. HDAC1 silencing also improved the sensitivity of tumors to DDP in vivo. USP5-dependentstabilization of HDAC1 contributed to cisplatin resistance and the malignancy of NSCLC by diminishing the levels of RILP acetylation, which suggested that targeting the HDAC1-USP5axis might represent a novel therapeutic strategy for overcoming DDP resistance in NSCLC patients.

KLF4 promotes cisplatin resistance by activating mTORC1 signaling in ovarian cancer

Ovarian cancer (OC) is a highly fatal gynecological malignancy worldwide, and cisplatin (CDDP) is commonly used as an initial chemotherapy treatment for OC. Nonetheless, most patients ultimately face recurrence because of resistance to cisplatin. Therefore, it is imperative to investigate the underlying mechanisms of drug resistance in OC. By analyzing differential gene expression using TCGA, GDSC, and GEO public databases, we discovered that increased KLF4 expression is strongly linked to chemotherapy resistance and unfavorable outcomes in OC. Subsequent validation through immunohistochemistry and western blotting confirmed the upregulated KLF4 expression in cisplatin-resistance OC cells lines and tissues. To investigate the function of KLF4, functional experiments were performed both in vitro and in vivo. We observed that knocking down KLF4 impaired cisplatin-resistance of OC. Further mechanism research based on RNA-seq and gene enrichment analysis revealed that interfering KLF4 suppressed the activation of mTORC1 pathway. Finally, rescue experiment demonstrated that using mTORC1 pathway inhibitor could attenuate the cisplatin resistance induced by the overexpression of KLF4. In conclusion, our research indicates that KLF4 promotes cisplatin resistance through the activation of mTORC1 signaling, and proposes that inhibiting KLF4 might serve as a viable therapeutic approach to overcoming drug resistance in ovarian cancer.

M6A-Modified SNRPA Controls Alternative Splicing of ERCC1 Exon 8 to Induce Cisplatin Resistance in Lung Adenocarcinoma.

Alternative splicing (AS) generates protein diversity and is exploited by cancer cells to drive tumor progression and resistance to many cancer therapies, including chemotherapy. SNRPA is first identified as a spliceosome-related gene that potentially modulates resistance to platinum chemotherapy. Both the knockout or the knockdown of SNRPA via CRISPR/Cas9 and shRNA techniques can reverse the resistance of cisplatin-resistant lung adenocarcinoma (LUAD) cells to cisplatin. SNRPA overexpression enhanced the resistance of cisplatin-sensitive LUAD cells. Gene Ontology (GO) analysis reveals that SNRPA is associated with DNA damage repair. Depletion of SNRPA induced ERCC1 exon 8 skipping and reduced ERCC1-XPF complex formation, whereas SNRPA overexpression exerted the opposite effect. siRNAs targeting isoforms containing ERCC1 exon 8 [ERCC1-E8 (+)] reversed SNRPA-enhanced cisplatin resistance and DNA damage repair. Furthermore, the IGF2BP protein, an m6A reader, and the ELAVL1 protein, an RNA stabilizer recruited by IGF2BP1, are found to bind to the SNRPA mRNA. ELAVL1 promoted cisplatin resistance, DNA repair and ERCC1-E8 (+) expression in an SNRPA-dependent manner. In a mouse xenograft model, SNRPA-KO CRISPR enhanced the sensitivity of LUAD cells to cisplatin. Overall, this study illuminates the role of SNRPA in platinum-based drug resistance, thereby providing a novel avenue to potentially enhance chemosensitivity and improve the prognosis of patients with LUAD.

ETS1 promotes cisplatin resistance of NSCLC cells by promoting GRP78 transcription.

Non-small cell lung cancer (NSCLC) is a common malignant tumor characterized by rapid growth and invasive power. Glucose regulatory protein 78 (GRP78) is important in cancer cell progression. Here, this study aimed to explore the effect and mechanism of GRP78 on cisplatin (DDP) resistance of NSCLC cells. qRT-PCR and Western blot detected the expression of genes and proteins. Flow cytometry was used to analyze endoplasmic reticulum stress (ERS) induced by DDP in NSCLC. Cell proliferation and apoptosis were examined using cell counting kit-8 (CCK8), cell cloning, and flow cytometry, respectively. Chromatin immunoprecipitation assay (CHIP) and dual-luciferase reporter assays were performed to determine the binding of ETS1 and GRP78 promoter. Mouse xenograft models were constructed for in vivo analysis. ERS was induced by DDP in NSCLC cells. GRP78 were upregulated in DDP-resistant NSCLC tissues, and knockdown of GRP78 suppressed DDP resistance, clone formation, promoted apoptosis, and inhibited ERS in DDP-resistant NSCLC cells. ETS1 knockdown repressed GRP78 expression and NSCLC tumor growth. Interestingly, ETS1 played a role in DDP-resistant NSCLC via GRP78. ETS1 inhibits cisplatin sensitivity of NSCLC cells by promoting GRP78 transcription.

Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3

HighlightsFOXO3 was decreased, while LA and FBXO22 were increased in NSCLC patients.LA promoted cisplatin resistance in NSCLC in vitro and in vivo.SQFZ inhibited LA-induced cisplatin resistance in NSCLC by regulating FOXO3.FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ.SQFZ inhibited cisplatin resistance in NSCLC by FOXO3/FBXO22/p53 axis.

NPR1 promotes cisplatin resistance by inhibiting PARL-mediated mitophagy-dependent ferroptosis in gastric cancer

Cisplatin-based chemotherapy serves as the standard of care for individuals with advanced stages of gastric cancer. Nevertheless, the emergence of chemoresistance in GC has detrimental impacts on prognosis, yet the underlying mechanisms governing this phenomenon remain elusive. Level of mitophagy and ferroptosis of GC cells were detected by fluorescence, flow cytometry, GSH, MDA, Fe2+ assays, and to explore the specific molecular mechanisms between NPR1 and cisplatin resistance by performing western blot and coimmunoprecipitation (co-IP) assays. These results indicates that NPR1 positively correlated with cisplatin-resistance and played a crucial part in conferring resistance to cisplatin in gastric cancer cells. Mechanistically, NPR1 affected levels of mitophagy and ferroptosis in human cisplatin-resistance GC cells with cisplatin treatment. Specifically, NPR1 inhibited mitophagy-dependent ferroptosis by reducing the ubiquitination-mediated degradation of PARL; moreover, NPR1 promoted PARL stabilization by disrupting the PARL–MARCH8 complex, which ultimately led to the development of chemoresistance in GC cells. Considering our findings, NPR1 appears to play an important role in chemotherapy for GC. NPR1 could potentially be used to overcome chemotherapy resistance.Graphical 1. NPR1 is highly expressed in cisplatin-resistant GC cells and promotes the cisplatin resistance.2. According to IP-MS, NPR1 inhibits mitophagy-dependent ferroptosis through its downstream protein PARL.3. NPR1 promoted PARL stabilization by disrupting the PARL–MARCH8 complex to inhibit the ubiquitination-mediated degradation of PARL.

SHCBP1 promotes cisplatin resistance of ovarian cancer through AKT/mTOR/Autophagy pathway.

Ovarian cancer caused the highest cancer-related mortality among female reproductive system malignancies. Platinum-based chemotherapy is still the footstone of the chemotherapy for ovarian cancer. However, the molecular mechanisms underlying cisplatin insensitivity and resistance remain unclear. SHC SH2 domain-binding protein 1 (SHCBP1) plays critical roles in the progression and drug resistance of different types of cancer. However, the biological function of SHCBP1 in ovarian cancer progression and cisplatin resistance remains obscure. In this study, we found that SHCBP1 was upregulated in ovarian cancer and the upregulated SHCBP1 has growth-promoting effect on ovarian cancer cells. Furthermore, SHCBP1 silencing sensitize ovarian cancer cells to cisplatin (hereafter referred to as CDDP). Mechanism analysis revealed that SHCBP1 activated the Akt/mTOR pathway and further inhibited autophagy in ovarian cancer cells. Meanwhile, autophagy inhibitors combined with SHCBP1 knockdown enhances CDDP sensitivity. In addition, knockdown of SHCBP1 restricted the proliferation of tumors and increased the cisplatin sensitivity in vivo. These findings suggested that upregulated SHCBP1 promoted the proliferation and CDDP resistance of ovarian cancer. The combination of SHCBP1 inhibition and cisplatin treatment might lead to substantial progress in ovarian cancer targeted therapy.

KLF1 Activates RAC3 to Mediate Fatty Acid Synthesis and Enhance Cisplatin Resistance in Bladder Cancer Cells.

While cisplatin remains a frontline treatment for bladder cancer (BCa), the onset of resistance greatly hampers its effectiveness. RAC3 is closely linked to chemoresistance in cancer cells, but its specific role in cisplatin resistance within BCa is still elusive. RAC3 expression in BCa was analyzed using bioinformatics and quantitative polymerase chain reaction (qPCR). The gene set enrichment analysis (GSEA) identified RAC3-enriched pathways and the correlation between RAC3 and fatty acid synthase (FASN), a gene involved in fatty acid synthesis. Potential upstream transcription factors of RAC3 were predicted and their interaction with RAC3 was confirmed via dual-luciferase and chromatin immunoprecipitation (ChIP) assays. T24/DDP, a cisplatin-resistant BCa cell line, was established to probe into the regulatory role of RAC3 in cisplatin resistance. Cell proliferation was evaluated by colony formation and the IC50 values after cisplatin treatment were determined using cell counting kit-8 (CCK-8). The levels of free fatty acids and triglycerides (TGs), as well as the expression of DGAT2 and FASN proteins, were measured to gauge the extent of fatty acid synthesis in cells. Elevated expression of RAC3 was observed in BCa and the cisplatin-resistant BCa cells (T24/DDP). The knockdown of RAC3 within T24/DDP cells was demonstrated to counteract cisplatin resistance. Subsequent analyses identified RAC3 as being notably enriched in the fatty acid synthesis pathway, with Kruppel-like factor 1 (KLF1) emerging as a key upstream regulator. The overexpression of RAC3 was correlated with increased cisplatin resistance in T24/DDP cells, an effect that was mitigated by the addition of the FASN inhibitor, Orlistat. Furthermore, the downregulation of KLF1 suppressed RAC3 expression, disrupted fatty acid synthesis, and attenuated cisplatin resistance in T24/DDP cells. Conversely, the co-overexpression of RAC3 counteracted the effects conferred by KLF1 knockdown. Our study has validated that KLF1 activates RAC3 to mediate fatty acid synthesis and promote cisplatin resistance in BCa, suggesting the KLF1/RAC3 axis as a potential target for combating cisplatin-resistant BCa.

Quercetin represses cholesterol metabolism and mitigates resistance to cisplatin in oral squamous cell carcinoma by regulating AGR2/AKT/SREBP2 axis

PurposeThis study aimed to explore the effects of quercetin on cholesterol metabolism and cisplatin sensitivity in oral squamous cell carcinoma (OSCC) cell line (CAL27) and investigate the potential molecular mechanisms. MethodsCAL27 cells were exposed to quercetin or cisplatin after upregulation or downregulation of AGR2. The expression of proteins and genes associated with cholesterol metabolism were assessed. The levels of cholesterol and LDL were also measured, and the cisplatin sensitivity of CAL27 cells was analyzed. ResultsRNA high-throughput sequencing revealed that after treatment with quercetin, the expression of AGR2 was significantly reduced in cisplatin-resistant CAL27 cells (CAL-27R), which was associated with lipid metabolism. AGR2 deletion ameliorated but its overexpression exacerbated cisplatin resistance and cholesterol metabolism, evidenced by changes in SQLE, HMGCS, LDLR, and n-SREBP2 expression and cholesterol and LDL levels. Moreover, AGR2 promoted cisplatin resistance by activating the AKT signaling pathway and enhancing SREBP2-mediated cholesterol metabolism. Quercetin increased cisplatin sensitivity by repressing cholesterol metabolism but suppressed the AGR2/AKT/SREBP2 signaling pathway in a concentration-dependent manner. These effects were partly reversed by AGR2 overexpression and AKT activation. ConclusionOur findings demonstrated that quercetin inhibits cholesterol metabolism and cisplatin resistance in CAL27 cells by modulating the AGR2/AKT/SREBP2 axis.

Circ_0008315 promotes tumorigenesis and cisplatin resistance and acts as a nanotherapeutic target in gastric cancer

IntroductionCisplatin-based chemotherapy is one of the fundamental therapeutic modalities for gastric cancer (GC). Chemoresistance to cisplatin is a great clinical challenge, and its underlying mechanisms remain poorly understood. Circular RNAs (circRNAs) are involved in the pathophysiology of multiple human malignancies.MethodsHigh-throughput sequencing was performed to determine the differentially expressed profile of circRNA in GC tissues and cisplatin-resistant GC cells. Quantitative real-time polymerase chain reaction and Fluorescence in situ hybridization was utilized to confirm the dysregulation of circ_0008315 in GC tissues. To evaluate the prognostic significance of circ_0008315 in GC, we used Kaplan-Meier plot. The self-renewal ability of drug-resistant GC cell was verified through tumor sphere formation assay. GC organoids were constructed to simulate the tumor microenvironment and verified the function of circ_0008315 in cisplatin resistance of gastric cancer. In vivo evaluation was conducted using patient-derived xenograft models. Dual-luciferase reporter gene, RNA immunoprecipitation and miRNA pull-down assays were employed to investigate the molecular mechanisms of circ_0008315 in GC.ResultsWe revealed that a novel circRNA hsa_circ_0008315 was upregulated in GC and cisplatin-resistant GC cells. Elevated circ_0008315 was also observed in cisplatin-resistant GC organoid model. High circ_0008315 expression predicted unfavorable survival outcome in GC patients. Downregulation of circ_0008315 expression inhibited proliferation, mobility, and epithelial-mesenchymal transition of GC cells in vitro and in vivo. Reducing circ_0008315 expression in cisplatin-resistant GC organoid model reversed cisplatin resistance. Mechanistically, circ_0008315 modulated the stem cell properties of GC through the miR-3666/CPEB4 signaling pathway, thereby promoting cisplatin resistance and GC malignant progression. Furthermore, we developed PLGA-PEG nanoparticles targeting circ_0008315, and the nanoparticles could effectively inhibit GC proliferation and cisplatin resistance.ConclusionCirc_0008315 exacerbates GC progression and cisplatin resistance, and can be used as a prognostic predictor. Circ_0008315 may function as a promising nanotherapeutic target for GC treatment.Graphical

MUL1 identified as mitochondria-linked biomarker promoting cisplatin resistance in OC cells

Ovarian cancer (OC) ranks among the prevalent tumors affecting the female reproductive system. The aim of this study was to evaluate mitochondria-associated platinum resistance genes using organoid models. Univariate Cox regression, LASSO and multivariate Cox regression analyses were performed on The Cancer Genome Atlas (TCGA) database to construct 2-gene prognostic signature (MUL1 and SSBP1), and GSE26712 dataset was used for external validation. In addition, the relationship between MUL1 and platinum resistance was examined by organoid culture, lentiviral transduction, CCK8 assay, and Western blot. The results showed that patients in the high-risk group exhibited significantly worse OS (P = 0.002, P = 0.017). Drug sensitivity analysis revealed that platinum resistance increased with the upregulation of MUL1 expression (Cor = 0.5154, P = 0.02). Our experimental findings demonstrated that knockout of the MUL1 gene significantly increased apoptosis and enhanced the sensitivity of the OC cell line A2780 to cisplatin. Through this study, we have provided strong evidence for further research on prognostic risk factors and individualized treatment in OC patients, and provided new insights into addressing platinum resistance in OC.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer

BackgroundElevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.MethodsWe developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.ResultsModel simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects.ConclusionsThis work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

The impact of SOX4-activated CTHRC1 transcriptional activity regulating DNA damage repair on cisplatin resistance in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the predominant subtype within the spectrum of lung malignancies. CTHRC1 has a pro-oncogenic role in various cancers. Here, we observed the upregulation of CTHRC1 in LUAD, but its role in cisplatin resistance in LUAD remains unclear. Bioinformatics analysis was employed to detect CTHRC1 and SRY-related HMG-box 4 (SOX4) expression in LUAD. Gene Set Enrichment Analysis predicted the enriched pathways related to CTHRC1. JASPAR and MotifMap databases predicted upstream transcription factors of CTHRC1. Pearson analysis was conducted to analyze the correlation between genes of interest. The interaction and binding relationship between CTHRC1 and SOX4 were validated through dual-luciferase and chromatin immunoprecipitation assays. Quantitative real-time polymerase chain reaction determined the expression of CTHRC1 and SOX4 genes. CCK-8 was performed to assess cell viability and calculate IC50 value. Flow cytometry examined the cell cycle. Comet assay and western blot assessed DNA damage. CTHRC1 and SOX4 were upregulated in LUAD. CTHRC1 exhibited higher expression in cisplatin-resistant A549 cells compared to cisplatin-sensitive A549 cells. Knockdown of CTHRC1 enhanced DNA damage during cisplatin treatment and increased the sensitivity of LUAD cells to cisplatin. Additionally, SOX4 modulated DNA damage repair (DDR) by activating CTHRC1 transcriptional activity, promoting cisplatin resistance in LUAD cells. SOX4 regulated DDR by activating CTHRC1, thereby enhancing cisplatin resistance in LUAD cells. The finding provides a novel approach to address clinical cisplatin resistance in LUAD, with CTHRC1 possibly serving as a candidate for targeted therapies in addressing cisplatin resistance within LUAD.

Atractyloside inhibits gefitinib‑resistant non‑small‑cell lung cancer cell proliferation.

Atractyloside is a traditional Chinese medicine used to treat nasal congestion, and allergic rhinitis; however, its effects on cancer are unknown. Non-small cell lung cancer (NSCLC) is associated with high mortality rates worldwide, and relapse due to epidermal growth factor receptor mutations is a problem in clinical therapy. Therefore, novel biomarkers are required for the diagnosis and treatment of NSCLC. Brother of the regulator of imprinted sites (BORIS; also known as CTCFL) is a potential therapeutic target in NSCLC. BORIS promotes cisplatin resistance and it has been suggested that it may account for multidrug resistance. The present study examined BORIS expression in tyrosine kinase inhibitor (TKI)-resistant NSCLC cells. Subsequently, small interfering RNA was used to knock down BORIS expression, and the effects of this knockdown were assessed on TKI-resistant NSCLC cell viability. The present study also investigated the effect of atractyloside on the proliferation of NSCLC cells using MTT assay. The results of the present study indicated that the inhibition of BORIS or its related downstream pathways may have potential for the treatment of TKI-resistant NSCLC. In addition, atractyloside mimicked BORIS knockdown, regulated its downstream genes and inhibited the proliferation of TKI-resistant NSCLC cells. In conclusion, the findings of the present study supported the potential application of atractyloside in TKI-resistant NSCLC therapy.

Retracted] Long non‑coding RNA receptor activator of nuclear factor‑κB ligand promotes cisplatin resistance in non‑small cell lung cancer cells.

[This retracts the article DOI: 10.3892/etm.2021.9949.].

UBA5 inhibition restricts lung adenocarcinoma via blocking macrophage M2 polarization and cisplatin resistance

UBA5, a ubiquitin-like activated enzyme involved in ufmylation and sumoylation, presents a viable target for pancreatic and breast cancer treatments, yet its role in lung adenocarcinoma (LUAD) remains underexplored. This study reveals UBA5's tumor-promoting effect in LUAD, as evidenced by its upregulation in patients and positive correlation with TNM stages. Elevated UBA5 levels predict poor outcomes for these patients. Pharmacological inhibition of UBA5 using DKM 2–93 significantly curtails the growth of A549, H1299, and cisplatin-resistant A549 (A549/DDP) LUAD cells in vitro. Additionally, UBA5 knockdown via shRNA lentivirus suppresses tumor growth both in vitro and in vivo. High UBA5 expression adversely alters the tumor immune microenvironment, affecting immunostimulators, MHC molecules, chemokines, receptors, and immune cell infiltration. Notably, UBA5 expression correlates positively with M2 macrophage infiltration, the predominant immune cells in LUAD. Co-culture experiments further demonstrate that UBA5 knockdown directly inhibits M2 macrophage polarization and lactate production in LUAD. Moreover, in vivo studies show reduced M2 macrophage infiltration following UBA5 knockdown. UBA5 expression is also associated with increased tumor heterogeneity, including tumor mutational burden, microsatellite instability, neoantigen presence, and homologous recombination deficiency. Experiments indicate that UBA5 overexpression promotes cisplatin resistance in vitro, whereas UBA5 inhibition enhances cisplatin sensitivity in both in vitro and in vivo settings. Overall, these findings suggest that targeting UBA5 inhibits LUAD by impeding cancer cell proliferation, M2 macrophage polarization, and cisplatin resistance.

Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells

Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.

HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma.

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.