CDDP Resistance Research Articles

Dual–target platinum(IV) complexes reverse cisplatin resistance in triple negative breast via inhibiting poly(ADP–ribose) polymerase (PARP–1) and enhancing DNA damage

Platinum(II)–based drugs play an important role in many chemotherapeutic protocols, but their further clinical applications are hindered by the development of drug resistance and serious side effects. Therefore, to reverse cisplatin (CDDP) resistance in tandem with reduced side effects, nine novel platinum(IV) complexes modified with key pharmacophore of Olaparib were synthesized and evaluated for biological activities. Among them, the optimal complex 8–2 showed good inhibitory activity against PARP–1 and superior anticancer effects over CDDP on parental (MDA–MB–231, IC50 = 1.13 μM) and CDDP –resistant triple–negative breast cancer (TNBC) cell line (MDA–MB–231/CDDP, IC50 = 1.72 μM). Detailed mechanisms revealed that compared with Olaparib and CDDP, the enhanced intracellular accumulation of 8–2 could efficiently reverse CDDP resistance in MDA–MB–231/CDDP cells via inhibiting DNA repair–associated mechanisms, enhancing DNA damage, and activating mitochondrion–dependent apoptosis pathway. Furthermore, 8–2 obtained higher tumor growth inhibition rate (64.1 %) than CDDP (26.5 %) in MDA–MB–231/CDDP xenografts, but it did not induce significant toxicity in vivo and in intro, making it a potential drug candidate for the treatment of TNBC.

Inhibition of JNK/c-Jun-ATF2 Overcomes Cisplatin Resistance in Liver Cancer through down-Regulating Galectin-1.

Due to drug resistance, the clinical response to cisplatin (CDDP) from patients with liver cancer is unsatisfactory. The alleviation or overcoming of CDDP resistance is an urgent problem to be solved in clinics. Tumor cells rapidly change signal pathways to mediate drug resistance under drug exposure. Here, multiple phosphor-kinase assays were performed and c-Jun N-terminal kinase (JNK) was activated in liver cancer cells treated with CDDP. The high activity of the JNK promotes poor progression and mediates cisplatin resistance in liver cancer, leading to a poor prognosis of liver cancer. Mechanistically, the highly activated JNK phosphorylated c-Jun and ATF2 formed a heterodimer to upregulate the expression of Galectin-1, leading to promoting cisplatin resistance in liver cancer. Importantly, we simulated the clinical evolution of drug resistance in liver cancer by continuous CDDP administration in vivo. In vivo bioluminescence imaging showed the activity of JNK gradually increased during this process. Moreover, the inhibition of JNK activity by small molecular or genetic inhibitors enhanced DNA damage and overcame CDDP resistance in vitro and in vivo. Collectively, our results underline that the high activity of JNK/c-Jun-ATF2/Galectin-1 mediates cisplatin resistance in liver cancer and provides an optional scheme for dynamic monitoring of molecular activity in vivo.

LINC00470 represses cell autophagy and cisplatin sensitivity of glioma via suppressing PTEN expression.

Glioma is one of primary brain tumours which has the worst clinical prognoses of patients. As an alternative chemotherapeutic drug for malignant glioma, the therapeutic effect of cisplatin (CDDP) is devastatingly affected due to resistance in patients. In this study, we investigated the effect of LINC00470/PTEN on the CDDP sensitivity of glioma cells. Differentially expressed lncRNAs and the downstream regulators in glioma tissue were obtained via bioinformatics analysis. LINC00470 and PTEN mRNA expression levels were detected using qRT-PCR. IC50 values of glioma cells were examined using Cell Counting Kit-8 (CCK-8). Cell apoptosis was revealed by flow cytometry. The expression level of autophagy-related protein was detected by western blot. Intracellular autophagosome formation was detected by immunofluorescence staining, and the methylation level of PTEN promoter was detected via methylation-specific PCR (MSP). Through the above steps, we found that LINC00470 was highly expressed in glioma cells, and the survival rate of patients was reduced in the presence of high expression of LINC00470. Silenced LINC00470 promoted LC3 II expression and autophagosome formation, and facilitated cell apoptosis to inhibit resistance to CDDP. While silenced PTEN could successfully reverse the previous effects on glioma cells. Based on the above, LINC00470 repressed cell autophagy by constraining PTEN, thereby enhancing CDDP resistance of glioma cells.

Atorvastatin improves cisplatin sensitivity through modulation of cholesteryl ester homeostasis in breast cancer cells.

Acquired treatment resistance is a significant problem in breast cancer management, and alterations in lipid metabolism have been proposed to contribute to the development of drug resistance as well as other aspects of tumor progression. The present study aimed to identify the role of cholesterol metabolism in MCF-7 and MDA-MB-231 breast cancer cell response to cisplatin (CDDP) treatment in the acute setting and in a model of CDDP resistance. MCF-7 (luminal A), MDA-MB-231 (triple-negative) and CDDP-resistant MDA-MB-231 (MDACR) cell lines were grown in the presence or absence of CDDP in combination with atorvastatin (ATV), lipid depletion or low-density lipoprotein loading and were analyzed by a variety of biochemical and radiometric techniques. Co-administration of CDDP and ATV strongly reduced cell proliferation and viability to a greater extent than CDDP alone, especially in MDA-MB-231 cells. These findings were associated with reduced cholesteryl ester synthesis and storage in MDA-MB-231 cells. In MDACR cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared to naïve MDA-MB-231 cells and ATV treatment restored CDDP sensitivity, suggesting that aberrant ACAT-1 expression and associated changes in cholesterol metabolism contribute to CDDP resistance in MDA-MB-231 cells. These findings indicate that the elevated susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV, is associated with an increased reliance on cholesteryl ester availability. Our data from these cell culture-based studies identifies altered cholesterol homeostasis as an adaptive response to CDDP treatment that contributes to aggressiveness and chemotherapy resistance.

Response of the Urothelial Carcinoma Cell Lines to Cisplatin

Cisplatin (CDDP)-based chemotherapy is the standard of care in patients with muscle-invasive bladder cancer. However, in a large number of cases, the disease becomes resistant or does not respond to CDDP, and thus progresses and disseminates. In such cases, prognosis of patients is very poor. CDDP manifests its cytotoxic effects mainly through DNA damage induction. Hence, response to CDDP is mainly dependent on DNA damage repair and tolerance mechanisms. Herein, we have examined CDDP response in a panel of the urothelial carcinoma cell (UCC) lines. We characterized these cell lines with regard to viability after CDDP treatment, as well as kinetics of induction and repair of CDDP-induced DNA damage. We demonstrate that repair of CDDP-induced DNA lesions correlates, at least to some extent, with CDDP sensitivity. Furthermore, we monitored expression of the key genes involved in selected DNA repair and tolerance mechanisms, nucleotide excision repair, homologous recombination and translesion DNA synthesis, and show that it differs in the UCC lines and positively correlates with CDDP resistance. Our data indicate that CDDP response in the UCC lines is dependent on DNA damage repair and tolerance factors, which may, therefore, represent valuable therapeutic targets in this malignancy.

Pharmacogenomic Profiling of Cisplatin-Resistant and -Sensitive Human Osteosarcoma Cell Lines by Multimodal Targeted Next Generation Sequencing.

Cisplatin (CDDP) is a drug for high-grade osteosarcoma (HGOS) treatment. Several germline pharmacogenetic studies have revealed associations between single nucleotide polymorphisms (SNPs) and CDDP-based therapy response or CDDP-related toxicity in patients with HGOS. Whether these variants could play a biological role in HGOS cells has not been studied so far. The aim of this study was to explore 28 SNPs of 14 genes in 6 CDDP-resistant and 12 drug-sensitive human HGOS cell lines. An innovative multimodal targeted next generation sequencing (mmNGS) approach with custom primers designed for the most commonly reported SNPs of genes belonging to DNA repair, CDDP transport or detoxification, or associated with CDPP-related toxicity was applied. The mmNGS approach was validated by TaqMan genotyping assays and emerged to be an innovative, reliable tool to detect genetic polymorphisms at both the DNA and RNA level. Allele changes in three SNPs (ERCC2 rs13181 and rs1799793, ERCC1 rs11615) were identified on both DNA and RNA derived libraries in association with CDDP resistance. A change of the GSTP1 rs1695 polymorphism from AA to AG genotype was observed in the RNA of all six CDDP-resistant variants. These SNPs emerged to be causally associated with CDDP resistance in HGOS cells.

Exosome-mediated transfer of circ_0063526 enhances cisplatin resistance in gastric cancer cells via regulating miR-449a/SHMT2 axis.

Exosomes are critical mediators of intercellular communication. Exosomal circular RNAs (circRNAs) have been reported to play critical roles in the development of chemoresistance in various tumors, including gastric cancer. However, the role of exosomal circ_0063526 in cisplatin (CDDP) resistance of gastric cancer is still unclear. The expression of circ_0063526, microRNA-449a (miR-449a) and serine hydroxymethyltransferase 2 (SHMT2) mRNA was determined by quantitative real-time PCR (qRT-PCR). Cell viability was assessed by the Cell Counting Kit-8 assay. Cell migration and invasion were evaluated by the transwell assay and wound healing assay. Western blot assay was used to measure the protein expression of light Chain 3 (LC3) I/II, p62 and SHMT2. Exosomes were detected using transmission electron microscopy. The size distribution of exosomes was analyzed by nanoparticle tracking analysis. The interaction between miR-449a and circ_0063526 or SHMT2 was confirmed by a dual-luciferase reporter and RNA pull-down assays. Circ_0063526 expression was increased in gastric cancer tissues and cells and CDDP-resistant cells. Extracellular circ_0063526 could be packaged into exosomes and transmitted to sensitive cells, thus disseminating CDDP resistance. Knockdown of exosomal circ_0063526 inhibited CDDP resistance via suppressing migration, invasion and autophagy in gastric cancer cells. Moreover, circ_0063526 was identified as a molecular sponge of miR-449a to upregulate SHMT2 expression. Further, exosomal circ_0063526 regulated SHMT2 expression to enhance CDDP resistance of gastric cancer cells. Additionally, high expression of exosomal circ_0063526 in serum was associated with poor response to CDDP treatment in gastric cancer patients. Exosomal circ_0063526 facilitated CDDP resistance in gastric cancer via regulating the miR-449a/SHMT2 axis.

Cisplatin Resistance: Genetic and Epigenetic Factors Involved.

Cisplatin (CDDP) is the drug of choice against different types of cancer. However, tumor cells can acquire resistance to the damage caused by cisplatin, generating genetic and epigenetic changes that lead to the generation of resistance and the activation of intrinsic resistance mechanisms in cancer cells. Among them, we can find mutations, alternative splicing, epigenetic-driven expression changes, and even post-translational modifications of proteins. However, the molecular mechanisms by which CDDP resistance develops are not clear but are believed to be multi-factorial. This article highlights a description of cisplatin, which includes action mechanism, resistance, and epigenetic factors involved in cisplatin resistance.

CircUBAP2 inhibits cisplatin resistance in gastric cancer via miR-300/KAT6B axis.

Circular RNAs play an important role in regulating cisplatin (CDDP) resistance in gastric cancer (GC). The aim of this study was to examine the role and downstream regulation mechanisms of circUBAP2 in CDDP resistance of GC. The expression of circUBAP2 in GC and its correlation with the prognosis of GC patients were analyzed using qRT-PCR and the Kaplan-Meier plotter database. The effects of circUBAP2 on cell viability and apoptosis were investigated by Cell Counting Kit 8 assay and flow cytometry. The expressions of drug-resistance-related proteins, P-gp and MRP1, were detected by Western blot. The interaction between circUBAP2 and miR-300 was confirmed using RNA pulldown and immunoprecipitation assays. The correlation between miR-300 and KAT6B was assessed using dual-luciferase reporter assay and TCGA database. CircUBAP2 was downregulated in GC tissues and cell lines, and correlated with the poor prognosis of GC. In addition, circUBAP2 enhanced apoptosis but inhibited cell viability and the CDDP resistance of GC cells in vitro . CircUBAP2 acted as a sponge of microRNA-300 (miR-300) and was negatively correlated with miR-300. Moreover, the upregulation of miR-300 partially removed the effects of circUBAP2 on cell viability, apoptosis and CDDP resistance in GC cells. MiR-300 directly targeted to lysine acetyltransferase 6B (KAT6B), and KAT6B overexpression showed an inhibitory effect on cell viability and CDDP resistance of GC cells. Our data suggested that the circUBAP2/miR-300/KAT6B axis was involved in the inhibition of CDDP resistance in GC, which might provide a novel focus for potential GC therapy.

Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo.

Proteasome inhibition is an attractive approach for anticancer therapy. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used as a standard chemotherapy drug in the treatment of solid malignant tumors, such as cervical cancer, ovarian cancer, colorectal cancer, and lung cancer. However, the development of CDDP resistance largely limits its clinical application. Proteasome inhibitors may enhance traditional chemotherapy agent-induced cytotoxicity and apoptosis. Marizomib (NPI-0052, salinosporamide A, Mzb), a second-generation proteasome inhibitor, shows synergistic anticancer activity with some drugs. Currently, the effect of Mzb on cervical cancer cell proliferation remains unclear. In this study, we explored the role of Mzb in three cervical cancer cell lines, HeLa, CaSki, and C33A, representing major molecular subtypes of cervical cancer and xenografts. We found that Mzb alone showed noteworthy cytotoxic effects, and its combination with CDDP resulted in more obvious cytotoxicity and apoptosis in cervical cancer cell lines and xenografts. In order to investigate the mechanism of this effect, we probed whether Mzb alone or in combination with CDDP had a better antitumor response by enhancing CDDP-induced angiopoietin 1 (Ang-1) expression and inhibiting the expression of TEK receptor tyrosine kinase (Tie-2) in the Ang-1/Tie-2 pathway, FMS-like tyrosine kinase 3 ligand (Flt-3L) and stem cell factor (SCF) as identified by a cytokine antibody chip test. The results suggest that Mzb has better antitumor effects on cervical cancer cells and can sensitize cervical cancer cells to CDDP treatment both in vitro and in vivo. Accordingly, we conclude that the combination of CDDP with Mzb produces synergistic anticancer activity and that Mzb may be a potential effective drug in combination therapy for cervical cancer patients.

All-trans retinoic acid-mediated miR-30a up-regulation suppresses autophagy and sensitizes gastric cancer cells to cisplatin

AimsThe potential of all-trans retinoic acid (ATRA) in regulating some microRNAs (miRNAs) involved in multiple cancer-related pathways, including resistance to chemotherapeutics, may be a valuable idea for overcoming the CDDP resistance of GC cells. Main methodsTreatment of gastric AGS and MKN-45 cells with CDDP enriched the CDDP surviving cells (CDDP-SCs). The abilities of chemoresistance to CDDP drug, migration, either apoptosis or cell cycle distribution, spheroid body formation and changes at miRNA and protein levels were evaluated in vitro by MTT assay, colony formation assay, flow cytometry, tumor spheres culture, qRT-PCR and western blot assay in CDDP-SCs and ATRA-treated CDDP-SCs cells, respectively. Key findingsCDDP-based chemotherapy significantly reduced microRNA-30a (miR-30a) levels in GC cells. We also observed elevated autophagy activity in cancer cells that possess stem cell-like properties with overexpressed specific stem cell markers. Our extended study suggested that the reduction of miR-30a by CDDP treatment, is the possible underlying mechanism of enhanced autophagic activity, as demonstrated by enhancing autophagy-related protein beclin 1 and LC3-II/LC-I ratio. The addition of ATRA in the culture medium of GC cells increased the expression of miR-30a, and disturbed characteristic CSC-like properties. Additional studies revealed that the increased expression of miR-30a declined the expression level of its target gene, beclin 1, and beclin 1-mediated autophagy. This leads to promoted CDDP-induced GC cell apoptosis and G2/M cell cycle arrest. SignificanceOverall, miR-30a/autophagy signaling has a critical role in regulating the chemoresistance of GC cells that ATRA could modulate.

Circ_0017274 acts on miR-637/CDX2 axis to facilitate cisplatin resistance in gastric cancer.

Currently, a substantial amount of circular RNAs (circRNAs) are closely associated with cancer development and the occurrence of drug resistance, however, circ_0017274 in cisplatin (CDDP) resistance in gastric cancer (GC) has not been addressed. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were utilized for circ_0017274, microRNA-637 (miR-637) and caudal-related homeobox transcription factor 2 (CDX2) contents analysis. Analysis of IC50, proliferation, cell cycle, apoptosis, migration and invasion of GC cells using Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry or transwell assays. Interaction between miR-637 and circ_0017274 or CDX2 was validated under the application of luciferase reporter system, RNA immunoprecipitation (RIP) analysis, and pull-down assay. The effect of circ_0017274 on CDDP sensitivity in vivo was tapped by xenograft models. Circ_0017274 and CDX2 had higher content in CDDP-resistant GC tissues and cells, while miR-637 had lower content. CDDP resistance and development of GC cells were arrested when circ_0017274 level was reduced in vitro. MiR-637 acted as a target of circ_0017274, and miR-637 downregulation abated the phenomenon of elevated sensitivity of sh-circ_0017274 to CDDP. MiR-637 was also demonstrated to interact with CDX2 and to co-regulate CDDP sensitivity in GC cells. The xenograft models also established that circ_0017274 downregulation strengthened CDDP sensitivity and thus curtailed tumour growth in vivo. Circ_0017274 downregulation boosted CDDP sensitivity by acting on miR-637/CDX2 in CDDP-resistant GC cells.

Long non-coding RNA opa-interacting protein 5 antisense transcript 1 (LncRNA OIP5-AS1) promoted cisplatin resistance in nasopharyngeal carcinoma via the miR-378a-3p/nicotinamide N-methyltransferase axis

LncRNAs involve in chemoresistance of human cancers. However, the role and molecular mechanisms of lncRNA OIP5-AS1 in the chemoresistance of NPC are still unexplored. In our study, upregulated OIP5-AS1 was found in cisplatin (CDDP)-resistant NPC tumors and cell lines. Functional assays revealed OIP5-AS1 knockdown suppressed malignant behaviors, but stimulated apoptosis of CDDP-resistant NPC cells. Furthermore, we demonstrated OIP5-AS1 positively regulated NNMT by directly targeting miR-378a-3p. In addition, its inhibition partially abolished the inhibitory effects of OIP5-AS1 silencing on malignancy of CDDPresistant NPC cells, whereas NNMT knockdown reverse these effects. In sum, our results indicated OIP5-AS1 contributed to the CDDP resistance of NPC by sponging miR-378a-3p to increase NNMT expression.

Upregulation of exonuclease 1 caused by homology-dependent repair confers cisplatin resistance to gastric cancer cells.

The homology-dependent repair (HDR) pathway is involved in deoxyribonucleic acid (DNA) damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents, including cisplatin (CDDP). Here, we explored the interactions between exonuclease 1 (EXO1), a core gene in the HDR pathway, and CDDP resistance in gastric cancer (GC). Using bioinformatics analysis, we identified the HDR pathway as the most amplified pathway in DDR in GC. In addition, EXO1 was the core gene in the HDR pathway and showed the most significant amplification in GC. The amplification of EXO1 resulted in higher EXO1 expression in cancerous tissues, with malignant prognostic effects. Moreover, we upregulated or downregulated EXO1 in GC cells to examine its effects on the cell malignant phenotype and CDDP resistance in vitro and in vivo. The depletion of EXO1 inhibited cell proliferatory, migratory, and invasive activities, and provided apoptosis resistance to GC cells. EXO1 expression was elevated in CDDP-resistant cells. Ectopic expression of EXO1 increased the resistance of GC cells to CDDP, while downregulation of EXO1 increased the sensitivity of GC cells. Taken together, our study indicates that the HDR pathway is an important player in CDDP resistance in GC through the regulation of EXO1.

Exosomal CTCF Confers Cisplatin Resistance in Osteosarcoma by Promoting Autophagy via the IGF2-AS/miR-579-3p/MSH6 Axis.

Cancer-derived exosomes participate in carcinogenesis and progression of cancers, including metastasis and drug-resistance. Of note, CTCF has been suggested to induce drug resistance in various cancers. Herein, we aim to investigate the role of cisplatin- (CDDP-) resistant osteosarcoma- (OS-) derived exosomal CTCF in OS cell resistance to CDDP and its mechanistic basis. Differentially expressed transcription factors, long noncoding RNAs (lncRNAs), miRNAs, and genes in OS were retrieved using bioinformatics approaches. Exosomes were extracted from CDDP-resistant OS cells and then cocultured with parental OS cells, followed by lentiviral transduction to manipulate the expression of CTCF, IGF2-AS, miR-579-3p, and MSH6. We assessed the in vitro and in vivo effects on malignant phenotypes, autophagy, CDDP sensitivity, and tumor formation of OS cells. It was established that CTCF and IGF2-AS were highly expressed in CDDP-resistant OS cells, and the CDDP-resistant OS cell-derived exosomal CTCF enhanced IGF2-AS transcription. CDDP-resistant OS-derived exosomes transmitted CTCF to OS cells and increased CDDP resistance in OS cells by activating an autophagy-dependent pathway. Mechanistically, CTCF activated IGF2-AS transcription and IGF2-AS competitively bound to miR-579-3p to upregulate MSH6 expression. Additionally, the promoting function of exosomal CTCF-mediated IGF2-AS/miR-579-3p/MSH6 in OS cell resistance to CDDP was confirmed in vivo. Taken together, CDDP-resistant OS-derived exosomal CTCF enhanced resistance of OS cells to CDDP via activating the autophagy-dependent pathway, providing a potential therapeutic consideration for OS treatment.

Redox Mechanisms in Cisplatin Resistance of Cancer Cells: The Twofold Role of Gamma-Glutamyltransferase 1 (GGT1).

Cisplatin (CDDP) is currently employed for the treatment of several solid tumors, but cellular heterogeneity and the onset of drug resistance dictate that suitable biomarkers of CDDP sensitivity are established. Studies on triple-negative breast cancer (TNBC) have recently confirmed the involvement of gamma-glutamyltransferase 1 (GGT1), whose enzyme activity expressed at the cell surface favors the cellular resupply of antioxidant glutathione (GSH) thus offering cancer cells protection against the prooxidant effects of CDDP. However, an additional well-established mechanism depends on GGT1-mediated matabolism of extracellular GSH. It was in fact shown that glycyl-cysteine – the dipeptide originated by GGT1-mediated GSH metabolism at the cell surface – can promptly form adducts with exogenous CDDP, thus hindering its access to the cell, interactions with DNA and overall cytotoxicity. Both mechanisms: mainainance of intracellular GSH levels plus extracellular CDDP detoxication are likely concurring to determine GGT1-dependent CDDP resistance.

JMJD2C mediates the MDM2/p53/IL5RA axis to promote CDDP resistance in uveal melanoma

Chemotherapy resistance poses an obstacle for effective treatment of uveal melanoma. In this study, we aim to investigate the effects of jumonji domain containing 2C (JMJD2C)-mediated mouse double minute-2 homolog (MDM2)/p53/interleukin 5 receptor subunit alpha (IL5RA) axis on cisplatin (CDDP) resistance in uveal melanoma. RT-qPCR and Western blot assay were performed to determine their expression patterns in uveal melanoma cell line (MUM-2B) and CDDP-resistant cell line (MUM-2B/CDDP). The enrichment of H3K9me3 in MDM2 promoter region was examined by ChIP, and the binding between p53 and ubiquitin in MUM-2B cells testified by co-IP assay. Following overexpression or silencing of JMJD2C/MDM2/p53/IL5RA, the 50% concentration of inhibition (IC50) and the biological characteristics of MUM-2B and MUM-2B/CDDP cells were examined using CCK-8 assay, SA-β-gal staining, fluorescence-activated cell sorting analysis, and Transwell assay. Finally, the tumorigenicity of transplanted MUM-2B and MUM-2B/CDDP cells in nude mice was assessed. JMJD2C was documented to be highly expressed in uveal melanoma cells, promoting the CDDP resistance. Histone demethylase JMJD2C removed the H3K9me3 modification of MDM2 promoter, which promoted the expression of MDM2. MDM2 enhanced the IL5RA expression through stimulating the ubiquitination and degradation of p53, thus inducing CDDP resistance of uveal melanoma cells. Furthermore, the results of in vivo experiments revealed that JMJD2C mediated the MDM2/p53/IL5RA axis to expedite the growth of uveal melanoma and augment the CDDP resistance. Taken together, JMJD2C can induce histone demethylation to upregulate MDM2, thereby ubiquitinating p53 and upregulating IL5RA. As a consequence, CDDP resistance in uveal melanoma is ultimately accelerated.

Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance

Background To analyse the regulatory effect of Fusobacterium nucleatum (Fn) on NOD-like receptor protein 3 (NLRP3) and myeloid-derived suppressor cells (MDSCs) in oesophageal squamous cell carcinoma (ESCC) as well as its effect on cisplatin (CDDP) therapy and to explore its clinical significance. Methods Fn infection, NLRP3 expression and MDSCs infiltration in ESCC tissues were detected by RNAscope and immunohistochemistry (IHC). The correlation between these three factors and the clinicopathological features and survival of ESCC patients was analysed. A coculture system of human peripheral blood monocytes (PBMCs) and ESCC cells was established to simulate the tumour microenvironment. In vitro and in vivo models were used to analyse the effects of Fn on the percentage of MDSCs in the coculture system and the NLRP3 expression level and CDDP sensitivity of ESCC cells. Results Fn infection was consistent with high NLRP3 expression and MDSCs enrichment in ESCC tissues. Moreover, the survival time of ESCC patients was significantly shortened under Fn infection, high NLRP3 expression and MDSCs enrichment. In the in vitro and in vivo models, Fn induced abundant enrichment of MDSCs by inducing high expression of NLRP3 in ESCC cells and reducing the sensitivity of ESCC cells to CDDP. Conclusions Fn infection can induce high expression of NLRP3 in ESCC, lead to MDSCs enrichment, weaken the body's antitumour immunity, and lead to CDDP treatment resistance. The effective elimination of Fn and the inhibition of MDSCs enrichment may provide new strategies and treatments for ESCC. Highlights The survival of ESCC patients with Fn infection, high NLRP3 expression and MDSCs enrichment was significantly shortened. Fn infection could cause CDDP resistance in ESCC. Fn could induce the enrichment of MDSCs in the tumour microenvironment by activating NLRP3 in ESCC cells.

Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma.

Expression status of p53 and organic cation transporter 1 is correlated with poor response to preoperative chemotherapy in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. DNA-damaging drugs, such as cisplatin (CDDP) and 5-fluorouracil (5-FU), are most frequently used in preoperative chemotherapy for ESCC. However, the response to preoperative chemotherapy varies among patients. p53, encoded by TP53, participates in apoptotic pathways following chemotherapy with DNA-damaging drugs, and mutation of TP53 contributes to chemoresistance. Organic cation transporter 1 (OCT1) participates in the uptake of CDDP, and its reduced expression is associated with CDDP resistance. The aim of this study was to evaluate the predictive impact of the expression status of p53 and OCT1 in response to preoperative chemotherapy in ESCC.MethodsWe retrospectively assessed 66 ESCC patients who received preoperative chemotherapy with CDDP/5-FU (CF) or docetaxel/CDDP/5-FU (DCF). p53 and OCT1 expression in pretreatment biopsy specimens was immunohistochemically determined and correlated with histological response to preoperative chemotherapy.Resultsp53 with wild-type (p53WT-ex) and mutant-type (p53MT-ex) expression patterns was identified in 40.9% and 59.1% of patients, respectively. High expression of OCT1 (OCT1High) was detected in 45.5%, and the remaining 54.5% showed low expression (OCT1Low). In a univariate analysis of the entire cohort, p53MT-ex was significantly correlated with poor response (P = 0.026), whereas OCT1Low showed marginal significance (P = 0.091). In a combined analysis, tumors with either p53MT-ex or OCT1Low showed a significant correlation with poor response compared with tumors with both p53WT-ex and OCT1High (P < 0.001). The sensitivity, specificity, and accuracy of combined p53/OCT1 were 93.9%, 47.1%, and 81.8%, respectively. Multivariate analysis identified p53 (P = 0.017), OCT1 (P = 0.032), and combined p53/OCT1 (P < 0.001) as independent predictors of histological response. When samples were stratified according to chemotherapy regimen in the univariate analysis, combined p53/OCT1 was the only significant factor for poor response in the CF (P = 0.011) and DCF (P = 0.021) groups, whereas p53 showed no statistical significance.ConclusionsOur results suggest that either p53MT-ex or OCT1Low expression in pretreatment biopsy specimens may be a potential predictor of poor response to preoperative chemotherapy with the CF-based regimens in ESCC, although the specificity needs to be improved.