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

Abstract

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 (>80 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+) 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.

• Authors: G Tufo, A W E Jones, Z Wang, J Hamelin, N Tajeddine, D D Esposti, C Martel, C Boursier, C Gallerne, C Migdal, C Lemaire, G Szabadkai, A Lemoine, G Kroemer, C Brenner
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 21 Issue 5 Pg. 685-95 (May 2014) ISSN: 1476-5403 [Electronic] England
• PMID: 24464223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• PDIA4 protein, human
• PDIA6 protein, human
• Protein Disulfide-Isomerases
• Cisplatin

Topics

• Adenocarcinoma (drug therapy, enzymology, pathology)
• Adenocarcinoma of Lung
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• Humans
• Lung Neoplasms (drug therapy, enzymology, pathology)
• Protein Disulfide-Isomerases (metabolism)