Down-regulation of FAK and IAPs by laminin during cisplatin-induced apoptosis in testicular germ cell tumors.
The purpose of this present study was to investigate the role of inhibitor of apoptosis proteins (IAPs), their inhibitor, Smac, and the focal adhesion kinase (FAK) in the laminin enhancement of cisplatin-induced apoptosis in a testicular tumor germ cell line, NCCIT. We demonstrated that specifically in laminin-adherent NCCIT cells, cisplatin-induced apoptosis followed a significant decrease of c-IAP-2 protein expression and of both XIAP mRNA and protein expression. Smac expression was not modified in any tested conditions. We also found that FAK, which mediates the ECM-integrin antiapoptotic signal was down-regulated early in cells cultured on laminin. Our results provide a possible mechanistic explanation to cisplatin-induced apoptosis in NCCIT cells adhered on laminin. Cisplatin down-regulated FAK protein expression early, which therefore failed to activate c-IAP-2 and XIAP expression, resulting in a defect in the abrogation of the activation of caspases. Thus, the laminin signaling enhances the cisplatin-induced apoptosis, at least partly, through a down-regulation of survival signal molecules. Our data raise an interesting possibility that a therapeutic strategy targeting these survival molecules would be efficient to overcome chemo-resistance in testicular germ cell tumor.
Andjilani
Maoulana
M
Centre Régional Léon Bérard, 69373 Lyon, France.
Droz
Jean-Pierre
JP
Benahmed
Mohamed
M
Tabone
Eric
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000494:pharmacology*; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D012333:RNA, Messenger / Q000378:metabolism; D013736:Testicular Neoplasms; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D007797:Laminin; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D002945:Cisplatin