Cisplatin‐resistant HeLa Cells Are Resistant to Apoptosis via p53‐dependent and ‐independent Pathways

Cervical cancer, which commonly contains a wild-type p53 gene, is highly correlated with human papilloma virus (HPV) infection. Because the oncoprotein E6, derived from HPV, inhibits the function of p53 protein, the inhibition of apoptosis via the p53 pathway by HPV may be related to cisplatin (CDDP)-sensitivity in cervical cancer. We conducted the present study to determine whether and how HPV is related to CDDP-sensitivity in HPV he survival rate for patients with uterine cervical cancer has not improved over the past 20 years, during which radiation therapy has been used for patients with advanced cancer. 1)However, platinum-based chemotherapy has recently been proved to be an effective therapy for cervical cancer.2, 3) Our previous study suggested that intra-arterial infusion of cisplatin (CDDP) may improve the prognosis of patients with advanced cervical cancer, 4, 5) but its efficacy is limited by resistance of the tumor to anticancer agents. Many mechanisms have been postulated to explain chemoresistance, including decreased drug accumulation inside tumor cells, increased cellular detoxification, and increased DNA repair activity.6-8) Apoptosis also contributes to sensitivity to anti-cancer agents, including CDDP. 9,10) p53, which is known to be a cell cycle checkpoint protein, plays a regulatory role in the control of cell proliferation and apoptosis.11) Mutations in the p53 gene are known to be associated with the lack of response to anti-cancer drugs, including CDDP.12, 13) We previously found that p53 gene transduction increased sensitivity to CDDP in ovarian cancer cells with deletion of the p53 gene. Additionally, p53 gene transduction enhanced CDDP-induced apoptosis.12) Although cervical cancer commonly contains a wild-type p53 gene, it is highly correlated with human papilloma virus (HPV) infection.14) The product of the MDM2 oncogene is known to directly interact with p53 and to promote its ubiquitination and proteasomal degradation. 15,16) The MDM2-dependent pathway for degradation of p53 is inactive in HPV-positive cancer cells. 17) In HPV-positive cells, the E6 oncoprotein derived from HPV forms a complex with E6-associated protein (E6AP) that is a cellular ubiquitin-protein ligase. 16,17) p53 protein combines with E6-E6AP complex and then is exported from the nucleus after ubiquitination.18) Because the viral oncoprotein E6 inhibits the function of p53 protein, the inhibition of apoptosis via the p53 pathway by HPV may be related to CDDP-sensitivity in cervical cancer. However, the correlation between the presence of HPV and CDDPsensitivity has not been established.Chromosomal region maintenance 1 (CRM1), a receptor of nuclear export signal (NES), combines with NES and exports proteins from nucleus to cytoplasm through the nuclear membrane pore. Leptomycin B (LMB) specifically binds with CRM1 to inhibit the export of NES-containing proteins.19) A recent study showed that LMB inhibited the degradation of p53 and accumulated active p53 in the nucleus of cells containing wild-type p53. 20) There...

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“…9,10) p53, which is known to be a cell cycle checkpoint protein, plays a regulatory role in the control of cell proliferation and apoptosis.…”

Section: )mentioning

confidence: 99%

“…[6][7][8] Apoptosis also contributes to sensitivity to anti-cancer agents, including CDDP. 9,10) p53, which is known to be a cell cycle checkpoint protein, plays a regulatory role in the control of cell proliferation and apoptosis. 11) Mutations in the p53 gene are known to be associated with the lack of response to anti-cancer drugs, including CDDP.…”

Section: )mentioning

confidence: 99%

Leptomycin B enhances CDDP‐sensitivity via nuclear accumulation of p53 protein in HPV‐positive cells

et al. 2003

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“…These disparities could be caused by competition between p53R249S and p53 for an unknown mediator(s) in HEK293 and MCF7, which was necessary for p53 to regulate TSP50 gene expression. However, no such competition occurred in HeLa and MCF7/Adr cells because they contained either the mutated or attenuated p53 gene, respectively (20,40).…”

Section: Tsp50 Encodes a Protease And Is Regulated By P53mentioning

confidence: 99%

TSP50 Encodes a Testis-Specific Protease and Is Negatively Regulated by p53

Shan

Jurukovski

et al. 2007

Cancer Research

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Earlier studies suggested that TSP50 is a testis-specific gene that encodes a protein, which is homologous to serine proteases but differs in that threonine replaces serine in its catalytic triad. Most importantly, it was abnormally reactivated in many breast cancer biopsies tested. While further investigating its biochemical and cell biological natures, we found that TSP50 exhibited enzyme activity and was located in the endoplasmic reticulum and cytosol membrane. During our studies to elucidate the regulatory mechanisms related to its differential expression, we discovered a putative p53-binding site and several Sp1-binding sites in the TSP50 promoter, which led us to test if it was regulated by the p53 gene. We found that the p53 transgene negatively regulated the TSP50 promoter in diverse types of cell lines. This result was consistent with other observations: (a) p53 overexpression reduced endogenous TSP50 expression; and (b) breast cancer cell lines containing mutated p53, such as MCF7/Adr, or normal p53, such as MCF7, produced high or low levels of TSP50 transcripts, which was consistent with the fact that TSP50 promoter activity was much higher in MCF7/Adr than that in MCF7 cells. We also found that the quantity of Sp1 transcription factor was lower in MCF7/Adr than in MCF7 cells, which suggested that another mechanism (i.e., transcription factor modulation) was also involved in TSP50 differential expression. [Cancer Res 2007;67(3):1239-45]

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“…Sensitive No Change [42] Patients with BRCA mutation compared to healthy controls, mechanism not investigated H460 NSCLC ↑FHIT Adenovirus 0.57 1 [43] Fragile [45] Mechanism of Cisplatin sensitivity not investigated HeLa Ovarian ↑p53wt Adenovirus 0.68 0.93 [46] Increase in DNA fragmentation induced by cisplatin HFF Human Fibroblasts ↓RB E7 virus 0.53 0.93 [47] Mechanism of Cisplatin sensitivity not investigated MEF Mouse Fibroblasts ↓Xrcc2 Knockout mouse Sensitive No Change [48] Decrease in Homologous Recombination repair of DNA double strand breaks induced by cisplatin…”

Section: Brca1 Mutationmentioning

confidence: 99%

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

Stordal¹,

Davey

2009

CCDT

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A systematic review of cell models of acquired drug resistance not involving genetic manipulation showed that 80% of cell models had an inverse resistance relationship between cisplatin and paclitaxel [1] . Here we systematically review genetically modified cell lines in which the inverse cisplatin/paclitaxel resistance phenotype has resulted. This will form a short list of genes which may play a role in the mechanism of the inverse resistance relationship as well as potential markers for monitoring the development of resistance in the clinical treatment of cancer. The literature search revealed 91 genetically modified cell lines which report toxicity or viability/apoptosis data for cisplatin and paclitaxel relative to their parental cell lines. This resulted in 26 genes being associated with the inverse cisplatin/paclitaxel phenotype. The gene with the highest number of genetically modified cell lines associated with the inverse resistance relationship was BRCA1 and this gene is discussed in detail with reference to chemotherapy response in cell lines and in the clinical treatment of breast, ovarian and lung cancer. Other genes associated with the inverse resistance phenotype included dihydrodiol dehydrogenase (DDH) and P-glycoprotein. Genes which caused cross resistance or cross sensitivity between cisplatin and paclitaxel were also examined, the majority of these genes were apoptosis associated genes which may be useful for predicting cross resistance. We propose that BRCA1 should be the first of a panel of cellular markers to predict the inverse cisplatin/paclitaxel resistance phenotype.3

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Cisplatin‐resistant HeLa Cells Are Resistant to Apoptosis via p53‐dependent and ‐independent Pathways

Cited by 45 publications

References 27 publications

Leptomycin B enhances CDDP‐sensitivity via nuclear accumulation of p53 protein in HPV‐positive cells

Leptomycin B enhances CDDP‐sensitivity via nuclear accumulation of p53 protein in HPV‐positive cells

TSP50 Encodes a Testis-Specific Protease and Is Negatively Regulated by p53

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

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