Cisplatin-resistance involves the defective processing of MEKK1 in human ovarian adenocarcinoma 2008/C13 cells.

Gebauer, Gerd; Mirakhur, Beloo; Nguyen, Quan; Shore, Scott K.; Simpkins, Henry; Dhanasekaran, N.

doi:10.3892/ijo.16.2.321

Cited by 19 publications

(23 citation statements)

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“…In keeping with this understanding, overexpression of bcl-2 is associated with cisplatin resistance, and this is likely facilitated by an increase in GSH levels (Hockenbery et al, 1993;Chiao et al, 1995) and compounded by the presence of mutant p53 (Strasser et al, 1994;Herod et al, 1996;Miyake et al, 1999). Similarly, increased levels of the antiapoptotic protein Bcl-xL are also observed in resistant tumor cells (Gebauer et al, 2000), possibly as a result of inhibition of the negative regulator Bad by the PI3-K/ Akt pathway (Hayakawa et al, 2000). Paradoxical findings, which indicate that bcl-2 overexpression is associated with either improved survival of ovarian cancer patients receiving cisplatin (Herod et al, 1996) or increased sensitivity of tumor cells to cisplatin (Beale et al, 2000), serve to demonstrate our present limited knowledge of the highly complex apoptotic process.…”

Section: Inhibitors Of Apoptosismentioning

confidence: 86%

“…In this regard, JNK MAPK activated via the MAP/ERK kinase kinase (MEKK1) phosphorylates p53, and a lack of this effect due to defective upstream activation of MEKK1 is the probable mechanism contributing to cisplatin resistance (Fuchs et al, 1998;Gebauer et al, 2000). The MAPK pathway also leads to the activation of a number of other transcription factors, such as c-Myc, c-Fos, and cJun (Robinson and Cobb, 1997;Martin-Blanco, 2000).…”

Section: Role Of Ras and Mapk Pathwaymentioning

confidence: 99%

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Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatinbased chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologicbased mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.

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Section: Inhibitors Of Apoptosismentioning

confidence: 86%

Section: Role Of Ras and Mapk Pathwaymentioning

confidence: 99%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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“…MEKK1 is also involved in apoptosis of colon cancer cells following chemotherapy (Soh et al, 2001). Furthermore, aberrant MEKK1 cleavage and subsequent apoptosis in certain ovarian adenocarcinomas leads to drug resistance (Gebauer et al, 2000). Dysregulation of apoptosis can also occur by mutation of genes involved in the death receptor pathways.…”

Section: Introductionmentioning

confidence: 99%

MEKK1-induced apoptosis requires TRAIL death receptor activation and is inhibited by AKT/PKB through inhibition of MEKK1 cleavage

et al. 2002

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MEK kinase 1 (MEKK1) induces apoptosis through the activation of caspases. The mechanism for MEKK1-induced apoptosis involves caspase-mediated cleavage of MEKK1, releasing a pro-apoptotic 91 kDa kinase fragment that serves to further amplify caspase activation in a feedback loop. Both cleavage of MEKK1 and increased expression of death receptor 4 (DR4, TRAILR1) and death receptor 5 (DR5, TRAILR2) occur following exposure of cells to genotoxins. Overexpression of kinase inactive MEKK1 inhibits MEKK1-mediated apoptosis and effectively blocks death receptor upregulation following etoposide treatment. Herein, we investigate the role of death receptor activation and the ability of AKT/PKB (AKT) to inhibit cell death in MEKK1-induced apoptosis. We show that by preventing DR4 and DR5 activation through expression of decoy receptor 1 (DcR1) and dominant negative FADD, we inhibit MEKK1-induced apoptosis. Furthermore, expression of 91 kDa MEKK1 increased DR4 and FAS mRNA and protein levels. MEKK1-induced apoptosis is amplified by blocking PI-3 kinase activation and overexpression of AKT blocked both MEKK1-induced apoptosis and caspase activation. AKT overexpression also prevented the cleavage of endogenous MEKK1 by genotoxins. AKT did not, however, block MEKK1-induced JNK activation, showing that regulation of the JNK pathway by MEKK1 is independent of its role in regulation of apoptosis. Thus, MEKK1-induced apoptosis requires TRAIL death receptor activation and is blocked by AKT through inhibition of MEKK1 cleavage.

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“…Recent studies have documented that CDDP triggers the activation of the JNK and p38 mitogenactivated protein kinase (MAPK) cascades in tumor cells or transformed cell lines (Benhar et al, 2001;Deschesnes et al, 2001;Gebauer et al, 2000;Pandey et al, 1996). Activation of JNK or p38 by CDDP was shown to promote apoptotic cell death (Benhar et al, 2001;Deschesnes et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cisplatin-induced activation of the EGF receptor

2002

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Cisplatin (CDDP) is an efficient DNA-damaging antitumor agent employed for the treatment of various human cancers. CDDP activates nuclear as well as cytoplasmatic signaling pathways involved in regulation of the cell cycle, damage repair and programmed cell death. Here we report that CDDP also activates a membrane-integrated protein, the epidermal growth factor receptor (EGFR). We show that EGFR is activated in response to CDDP in various types of cells that overexpress the receptor, including transformed human glioma cells and human breast tumor cells. CDDP-induced EGFR activation requires its kinase activity, as it can be blocked by an EGFR kinase inhibitor or by expression of a kinase dead receptor. We also show that CDDP-induced EGFR activation is independent of receptor ligand. CDDP induces the activation of c-Src, and EGFR activation is blocked by Src-family inhibitor PP1, suggesting that Src kinases mediate CDDP-induced EGFR activation. We propose that EGFR activation in response to CDDP is a survival response, since inhibition of EGFR activation enhances CDDP-induced death. These findings show that signals generated by DNA damage can modulate EGFR activity, and argue that interfering with CDDP-induced EGFR activation in tumor cells might be a useful approach to sensitize these cells to genotoxic agents.

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Cisplatin-resistance involves the defective processing of MEKK1 in human ovarian adenocarcinoma 2008/C13 cells.

Cited by 19 publications

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Cisplatin: mode of cytotoxic action and molecular basis of resistance

Cisplatin: mode of cytotoxic action and molecular basis of resistance

MEKK1-induced apoptosis requires TRAIL death receptor activation and is inhibited by AKT/PKB through inhibition of MEKK1 cleavage

Cisplatin-induced activation of the EGF receptor

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