Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells

Dw, Shen; Su, Andrew I.; Liang, Xiaoyan; Pai-Panandiker, Atmaram; Mm, Gottesman

doi:10.1038/sj.bjc.6601956

Cited by 47 publications

(49 citation statements)

References 29 publications

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“…Uptake of cisplatin can be governed by different mechanisms including passive diffusion, carrier-mediated transporting, and endocytosis (54). An elegant study has shown that several small GTPases (Rab 5, Rac 1, and Rho A) were down-regulated in cisplatin-resistant human hepatoma and epidermal carcinoma cells, demonstrating that GTPaseregulated endocytosis is an important factor in drug-resistance (55). Quantitative proteomic analysis in this study shows that Ras-related proteins Rab 5C and Rab 11B are down-regulated in A2780-DR cells as confirmed by Western blotting and qPCR.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Ras-related Protein Rab 5C-dependent Endocytosis and Glycolysis in Cisplatin-resistant Ovarian Cancer Cell Lines

Jin

Huo

Zheng

et al. 2014

Molecular & Cellular Proteomics

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Drug resistance poses a major challenge to ovarian cancer treatment. Understanding mechanisms of drug resistance is important for finding new therapeutic targets. In the present work, a cisplatin-resistant ovarian cancer cell line A2780-DR was established with a resistance index of 6.64. The cellular accumulation of cisplatin was significantly reduced in A2780-DR cells as compared with A2780 cells consistent with the general character of drug resistance. Quantitative proteomic analysis identified 340 differentially expressed proteins between A2780 and A2780-DR cells, which involve in diverse cellular processes, including metabolic process, cellular component biogenesis, cellular processes, and stress responses. Expression levels of Ras-related proteins Rab 5C and Rab 11B in A2780-DR cells were lower than those in A2780 cells as confirmed by real-time quantitative PCR and Western blotting. The short hairpin (sh)RNA-mediated knockdown of Rab 5C in A2780 cells resulted in markedly increased resistance to cisplatin whereas overexpression of Rab 5C in A2780-DR cells increases sensitivity to cisplatin, demonstrating that Rab 5C-dependent endocytosis plays an important role in cisplatin resistance. Our results also showed that expressions of glycolytic enzymes pyruvate kinase, glucose-6-phosphate isomerase, fructosebisphosphate aldolase, lactate dehydrogenase, and phosphoglycerate kinase 1 were down-regulated in drug resistant cells, indicating drug resistance in ovarian cancer is directly associated with a decrease in glycolysis. Furthermore, it was found that glutathione reductase were up-regulated in A2780-DR, whereas vimentin, HSP90, and Annexin A1 and A2 were down-regulated. Taken together, our results suggest that drug resistance in ovarian cancer cell line A2780 is caused by multifactorial traits, including the down-regulation of Rab 5C-dependent endocytosis of cisplatin, glycolytic enzymes, and vimentin, and up-regulation of antioxidant proteins, suggesting Rab 5C is a potential target for treatment of drug-resistant ovarian cancer. This constitutes a further step toward a comprehensive understanding of drug resistance in ovarian cancer.Molecular & Cellular Proteomics 13: 10.1074/ mcp.M113.033217, 3138-3151, 2014.Ovarian cancer is the major cause of death in women with gynecological cancer. Early diagnosis of ovarian cancer is difficult, while its progression is fast. The standard treatment is surgical removal followed by platinum-taxane chemotherapy. However, the efficacy of the traditional surgery and chemotherapy is rather compromised and platinum resistant cancer recurs in ϳ25% of patients within six months, and the overall five-year survival rate is about 31% (1-3). Virtually no efficient second line treatment is available. In order to increase survival rates from ovarian cancer and enhance patients' quality of life, new therapeutic targets are urgently required, necessitating a deeper understanding of molecular mechanisms of drug resistance.Mechanisms of drug-resistance in ovarian cancer have been extensi...

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Section: Discussionmentioning

confidence: 99%

Down-regulation of Ras-related Protein Rab 5C-dependent Endocytosis and Glycolysis in Cisplatin-resistant Ovarian Cancer Cell Lines

Jin

Huo

Zheng

et al. 2014

Molecular & Cellular Proteomics

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“…The difference in transferrin distribution between the CP-r and CP-s cells may result from defective endocytosis of the CP-r cells as demonstrated by our previous studies (32,35). Cisplatin passes through the plasma membrane and enters cells in part by endocytosis (36)(37)(38). We believe that multihydroxylated metallofullerene [Gd@C 82 (OH) 22 ] n nanoparticles reactivate endocytosis through their unique nanoscale properties.…”

Section: Intracellular Cisplatin Accumulation By Reactivating the Defmentioning

confidence: 99%

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

Lü

Meng

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

235

160

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Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C 82 (OH) 22 ] n nanoparticles, that [Gd@C 82 (OH) 22 ] n may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C 82 (OH) 22 ] n not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CPr PC-3-luc cells with [Gd@C 82 (OH) 22 ] n enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C 82 (OH) 22 ] n nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.A s a major chemotherapeutic agent for tumor treatment, cisplatin remains a cornerstone of the present-day chemotherapy regimens against not only epithelial malignancies but also a number of metastatic and advanced malignancies (1, 2). However, because of high toxicity and easy development of drug resistance, successful treatment with cisplatin often is limited (3,4). Following the discovery of ATP-binding cassette (ABC) transporters and their roles in drug resistance in various types of tumors (5), much research has been done to explore the relationship between ABC transporter activity and specific chemotherapeutics, including cisplatin. Because no ABC transporter has been identified for "pumping" cisplatin out of cisplatin-resistant human prostate cancer (CP-r) cells (6-8), it would be difficult to sensitize CP-r cells by using any known strategy that targets resistant cancer cells by inhibiting multidrug resistance (MDR)-associated proteins on plasma membrane of the CP-r cells. Diffusion has been considered as a pathway for cisplatin to penetrate plasma membrane. Recently, studies have indicated that cisplatin entered cells by endocytosis and other mechanisms (9-12).To increase susceptibility of cancer cells to cisplatin, i.e., to reverse drug resistance, many efforts have been made through chemical modification, gene therapy, vector delivery, and other means (2, 9, 13). Combination of traditional chemotherapy with nanotechnology may provide a promising alternative for novel cancer treatments. The use of nanoparticles to sensitize tumor cells to cisplatin in vitro and in vivo has been described recently (14-16). In these studies, cisplatin-encap...

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“…Many epigenetically silenced tumor suppressor gene involved in cancer-chemoresistance likely remain to be identified as most studies have focused on a limited number of candidate genes (Strathdee et al, 1999;Shen et al, 2004). Therefore, a microarray-based screening pairing the differential genetic profile of sensitive and CDDP-resistant cell lines with an epigenetic reactivation approach has the advantage of a global analysis that should preferentially identify epigenetically silenced genes as a result of acquired CDDP-chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

“…This includes lung cancer cells, in which MGMT, p16, RARb, TIMP-3 and DAPK have been reported as hypermethylated (Merlo et al, 1995;Esteller et al, 1999;Zochbauer-Muller et al, 2001). In addition, drug-induced DNA hypermethylation could be a mechanism of tumor cell response to chemotherapy agents (Nyce, 1997;Strathdee et al, 1999;Shen et al, 2004;Zhang et al, 2004). In both lung adenocarcinoma (HTB-54) and rhabdomyosarcoma human cells , pulse exposure to CDDP is associated with drug-induced DNA hypermethylation (Nyce, 1989), an event that has also been reported in vivo (Koul et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

et al. 2009

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Cisplatin-based chemotherapy is the paradigm of non-smallcell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (Po0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (Po0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment.

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Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells

Cited by 47 publications

References 29 publications

Down-regulation of Ras-related Protein Rab 5C-dependent Endocytosis and Glycolysis in Cisplatin-resistant Ovarian Cancer Cell Lines

Down-regulation of Ras-related Protein Rab 5C-dependent Endocytosis and Glycolysis in Cisplatin-resistant Ovarian Cancer Cell Lines

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

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