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Cell Death Differ. 2014 May;21(5):685-95. doi: 10.1038/cdd.2013.193. Epub 2014 Jan 24.

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

Author information

1
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
2
Department of Cell and Developmental Biology, University College London, London, UK.
3
APHP Hôpital P. Brousse, Biochimie et oncogénétique, INSERM U1004, Villejuif, France.
4
INSERM U848, Institut Gustave Roussy, Université Paris-Sud 11, PR1, 39 rue Camille Desmoulins, Villejuif, France.
5
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France [3] Montreal Heart Institute, Centre de Recherche, Montreal, Quebec, Canada.
6
IFR 141-IPSIT, Châtenay-Malabry, France.
7
1] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France [2] INSERM U 996, Châtenay-Malabry, France.
8
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Department of Biology, University of Versailles-St Quentin, Versailles, France.
9
1] Department of Cell and Developmental Biology, University College London, London, UK [2] Department of Biomedical Sciences, University of Padua, Padua, Italy.
10
1] INSERM U848, Institut Gustave Roussy, Université Paris-Sud 11, PR1, 39 rue Camille Desmoulins, Villejuif, France [2] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France [3] Metabolomics Platform, Institut Gustave Roussy, Villejuif, France [4] Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France [5] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.

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.

PMID:
24464223
PMCID:
PMC3978299
DOI:
10.1038/cdd.2013.193
[Indexed for MEDLINE]
Free PMC Article

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