The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.
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.
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
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Tufo
Department of Cell and Developmental Biology, University College London, London, UK.
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Jones
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
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Wang
APHP Hôpital P. Brousse, Biochimie et oncogénétique, INSERM U1004, Villejuif, France.
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Hamelin
INSERM U848, Institut Gustave Roussy, Université Paris-Sud 11, PR1, 39 rue Camille Desmoulins, Villejuif, France.
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Tajeddine
APHP Hôpital P. Brousse, Biochimie et oncogénétique, INSERM U1004, Villejuif, France.
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Esposti
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.
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Martel
IFR 141-IPSIT, Châtenay-Malabry, France.
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Boursier
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
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Gallerne
1] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France [2] INSERM U 996, Châtenay-Malabry, France.
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Migdal
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Department of Biology, University of Versailles-St Quentin, Versailles, France.
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Lemaire
1] Department of Cell and Developmental Biology, University College London, London, UK [2] Department of Biomedical Sciences, University of Padua, Padua, Italy.
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Szabadkai
APHP Hôpital P. Brousse, Biochimie et oncogénétique, INSERM U1004, Villejuif, France.
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Lemoine
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.
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Kroemer
1] INSERM UMR-S 769, LabEx LERMIT, Châtenay-Malabry, France [2] Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
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Brenner
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*
D000970:Antineoplastic Agents; C526505:PDIA4 protein, human; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases; D002945:Cisplatin