Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation.

Parker, Ricardo J.; Eastman, Alan; Bostick-Bruton, Frieda; Reed, Eddie

doi:10.1172/jci115080

Cited by 265 publications

(198 citation statements)

References 18 publications

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“…Several molecules have been implicated in cisplatin resistance, including decreased cellular detoxication (3,4), increased DNA repair (5), and mutations of p53 tumor suppressor gene (6,7). However, the mechanisms involved in cisplatin resistance are still poorly understood.…”

mentioning

confidence: 99%

AKT2 Inhibition of Cisplatin-induced JNK/p38 and Bax Activation by Phosphorylation of ASK1

Yuan

Feldman²,

Sussman³

et al. 2003

Journal of Biological Chemistry

183

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Cisplatin and its analogues have been widely used for treatment of human cancer. However, most patients eventually develop resistance to treatment through a mechanism that remains obscure. Previously, we found that AKT2 is frequently overexpressed and/or activated in human ovarian and breast cancers. Here we demonstrate that constitutively active AKT2 renders cisplatinsensitive A2780S ovarian cancer cells resistant to cisplatin, whereas phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 sensitizes A2780S and cisplatin-resistant A2780CP cells to cisplatin-induced apoptosis through regulation of the ASK1/JNK/p38 pathway. AKT2 interacts with and phosphorylates ASK1 at Ser-83 resulting in inhibition of its kinase activity. Accordingly, activated AKT2 blocked signaling downstream of ASK1, including activation of JNK and p38 and the conversion of Bax to its active conformation. Expression of nonphosphorylatable ASK1-S83A overrode the AKT2-inhibited JNK/p38 activity and Bax conformational changes, whereas phosphomimic ASK1-S83D inhibited the effects of cisplatin on JNK/p38 and Bax. Cisplatin-induced Bax conformation change was inhibited by inhibitors or dominant negative forms of JNK and p38. In conclusion, our data indicate that AKT2 inhibits cisplatin-induced JNK/p38 and Bax activation through phosphorylation of ASK1 and thus, plays an important role in chemoresistance. Further, regulation of the ASK1/JNK/p38/Bax pathway by AKT2 provides a new mechanism contributing to its antiapoptotic effects.Although cisplatin and its analogues, the DNA cross-linking agents, are first-line chemotherapeutic agents for the treatment of human ovarian and breast cancers, chemoresistance remains a major hurdle to successful therapy (1, 2). Several molecules have been implicated in cisplatin resistance, including decreased cellular detoxication (3, 4), increased DNA repair (5), and mutations of p53 tumor suppressor gene (6, 7). However, the mechanisms involved in cisplatin resistance are still poorly understood. A growing body of evidence indicates that defects in the intra-and extracellular survival/apoptotic pathways are an important cause of resistance to cytotoxic agents.Phosphatidylinositol 3-kinase (PI3K) 1 /Akt is a major cell survival pathway that has been extensively studied recently (8). PI3K is a heterodimer composed of a p85 regulatory and a p110 catalytic subunit and converts the plasma membrane lipid phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Pleckstrin homology domain-containing proteins, including Akt, accumulate at sites of PI3K activation by directly binding to phosphatidylinositol 3,4,-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Akt (also known as PKB) represents a subfamily of serine/threonine kinases. Three member of this family, including AKT1, AKT2, and AKT3, have been identified so far. Akt is activated in a PI3K-dependent manner by a variety of stimuli, including g...

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mentioning

confidence: 99%

AKT2 Inhibition of Cisplatin-induced JNK/p38 and Bax Activation by Phosphorylation of ASK1

Yuan

Feldman²,

Sussman³

et al. 2003

Journal of Biological Chemistry

183

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“…Second, the assay measures the ability of the repair systems to complete all steps in the process and actually generate a functional protein. Third, the reporter gene reactivation assay has previously been validated for cisplatin adduct repair (Sheibani et al, 1989;Jennerwein et al, 1991;Parker et al, 1991;Ali-Osman et al, 1994). One limitation of this assay system is that it reflects repair processes occurring in an extrachromosomal segment of DNA rather than in an endogenous gene.…”

Section: Discussionmentioning

confidence: 99%

Loss of DNA mismatch repair facilitates reactivation of a reporter plasmid damaged by cisplatin

Cenni

et al. 1999

Br J Cancer

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In addition to recognizing and repairing mismatched bases in DNA, the mismatch repair (MMR) system also detects cisplatin DNA adducts and loss of MMR results in resistance to cisplatin. A comparison was made of the ability of MMR-proficient and -deficient cells to remove cisplatin adducts from their genome and to reactivate a transiently transfected plasmid that had previously been inactivated by cisplatin to express the firefly luciferase enzyme. MMR deficiency due to loss of hMLH1 function did not change the extent of platinum (Pt) accumulation or kinetics of removal from total cellular DNA. However, MMR-deficient cells, lacking either hMLH1 or hMSH2, generated twofold more luciferase activity from a cisplatin-damaged reporter plasmid than their MMR-proficient counterparts. Thus, detection of the cisplatin adducts by the MMR system reduced the efficiency of reactivation of the damaged luciferase gene compared to cells lacking this detector. The twofold reduction in reactivation efficiency was of the same order of magnitude as the difference in cisplatin sensitivity between the MMR-proficient and -deficient cells. We conclude that although MMR-proficient and -deficient cells remove Pt from their genome at equal rates, the loss of a functional MMR system facilitates the reactivation of a cisplatin-damaged reporter gene. © 1999 Cancer Research Campaign

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“…This has been attributed to both enhancement of DNA repair efficiencies [47] and cellular antioxidant potential [48]. Firstly, in order to identify differences in cisplatin resistance in cell line models used here, we exposed PEO1 and PEO4 ovarian cancer cell lines to varying concentrations of cisplatin for 24h.…”

Section: Cisplatin Induced Cytotoxicity Is Partially Relieved By Neutmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation.

Cited by 265 publications

References 18 publications

AKT2 Inhibition of Cisplatin-induced JNK/p38 and Bax Activation by Phosphorylation of ASK1

AKT2 Inhibition of Cisplatin-induced JNK/p38 and Bax Activation by Phosphorylation of ASK1

Loss of DNA mismatch repair facilitates reactivation of a reporter plasmid damaged by cisplatin

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

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