Cisplatin Resistance Associated with PARP Hyperactivation

Michels, Judith; Vitale, Ilio; Galluzzi, Lorenzo; Adam, Julien; Olaussen, Ken A.; Kepp, Oliver; Senovilla, Laura; Talhaoui, Ibtissam; Guégan, Justine; Enot, David; Talbot, Monique; Robin, Angélique; Girard, Philippe; Oréar, Cédric; Lissa, Delphine; Sukkurwala, Abdul Qader; Garcia, Pauline; Behnam‐Motlagh, Parviz; Kohno, Kimitoshi; Wu, Gen Sheng; Brenner, Catherine; Dessen, Philippe; Saparbaev, Murat; Soria, Jean Charles; Castedo, Maria; Kroemer, Guido

doi:10.1158/0008-5472.can-12-3000

Cited by 145 publications

(134 citation statements)

References 48 publications

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“…5,16,22,35 Here, we found that this resistance phenotype correlate with gene expression regulation of several Figure 6 Caspase role in cell death elicited by PDIA4 and PDIA6 knockdown and CDDP. R1, R2 and R3 cells were treated only with siRNA PDIA6 for 48 h followed by 2 h of 50 mM caspase inhibitor Z-VAD or Z-LEVD and/or 48 h of 25 mM CDDP treatment.…”

Section: Discussionmentioning

confidence: 68%

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

et al. 2014

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Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (480 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca 2 þ fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

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Section: Discussionmentioning

confidence: 68%

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

et al. 2014

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“…Michels and colleagues analyzed several cisplatin-resistant cancer cell lines and found that a subset of these lines overexpress PARP1 and display hyperactivity of PARylation. Furthermore, a positive correlation was observed between the cellular PARylation and the sensitivity to PARP inhibitors (Michels et al, 2013). It should be noted that clinical experience thus far has shown that platinum-sensitive tumors are more likely to respond to PARP inhibitors than are platinumresistant or platinum-refractory diseases (Fong et al, 2010), so the clinical prospect of this observation remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

192

188

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Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

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“…Platinum drugs bind to DNA and the resulting complex induce lesion of DNA molecules, leading to cell death (OlaussenDunant et al, 2006). Therefore, proteins in DNA repair pathways can affect response to platinum drugs and influence the survival of patients (Parsons et al, 2005;OlaussenDunant et al, 2006;Rosell et al, 2007;KamalSoria et al, 2010;Michels et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Expression of ERCC1, MSH2 and PARP1 in Non-small Cell Lung Cancer and Prognostic Value in Patients Treated with Platinum-based Chemotherapy

Xie

He²,

Sun³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Purpose: To evaluate the prognostic value of the expression of excision repair cross-complementation group l (ERCC1), MutS protein homolog 2 (MSH2) and poly ADP-ribose polymerase 1 (PARP1) in non-small-cell lung cancer patients receiving platinum-based postoperative adjuvant chemotherapy. Methods: Immunohistochemistry was applied to detect the expression of ERCC1, MSH2 and PARP1 in 111 cases of non-small cell lung cancer paraffin embedded surgical specimens. Through og-rank survival analysis, we evaluated the prognostic value of the ERCC1, MSH2, PARP1 and the related clinicopathological factors. COX regression analysis was used to determine whether ERCC1, MSH2 and PARP1 were independent prognostic factors. Results: In the enrolled 111 non-small cell lung cancer patients, the positive expression rate of ERCC1, MSH2 and RARP1 was 33.3%, 36.9% and 55.9%, respectively. ERCC1 (P<0.001) and PARP1 (P=0.033) were found to be correlated with the survival time while there was no correlation for MSH2 (P=0.298). Patients with both ERCC1 and PARP1 negative cancer had significantly longer survival time than those with ERCC1 (P=0.042) or PARP1 (P=0.027) positive alone. Similalry, the survival time of patients with both ERCC1 and PARP1 positive cancer was shorter than those with ERCC1 (P=0.048) or PARP1 (P=0.01) positive alone. Conclusion: Patients with ERCC1 or PARP1 negative non-small cell lung cancer appear to benefit from platinum-based postoperative adjuvant chemotherapy.

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Cisplatin Resistance Associated with PARP Hyperactivation

Cited by 145 publications

References 48 publications

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

Trapping Poly(ADP-Ribose) Polymerase

Expression of ERCC1, MSH2 and PARP1 in Non-small Cell Lung Cancer and Prognostic Value in Patients Treated with Platinum-based Chemotherapy

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