Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation.
The inhibitor of apoptosis protein (IAP) survivin is overexpressed in many tumors but is absent in most normal adult tissues. We report high levels of survivin expression in small cell lung cancer (SCLC), and describe the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in survivin upregulation. Moreover, the cytoprotective function of survivin in response to the anti-cancer agent cisplatin (CDDP) was investigated. Negative modulation of PI3K/Akt using pharmacological inhibitors or dominant negative Akt (DN-Akt) decreased Akt kinase activity and resulted in decreased survivin expression and phosphorylation on Thr34, whereas transfection of constitutively active Akt (CA-Akt) increased survivin expression and phosphorylation. Interestingly, we found that treatment of SCLC cells with CDDP further increased survivin expression in a cell cycle independent manner by activation of Akt. CA-Akt or lentiviral survivin also inhibited apoptosis induced by CDDP, whereas DN-Akt or survivin-specific RNA interference sensitized cells to CDDP. We identified survivin as an anti-apoptotic protein in SCLC cells that is regulated by Akt, and demonstrate that treatment with the DNA damaging agent CDDP activates the PI3K/Akt/survivin pathway that in part protects cells from drug-induced apoptosis.
Laboratory of Molecular Oncology, Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
Larisa L
LL
Belyanskaya
Sally
S
Hopkins-Donaldson
Stefanie
S
Kurtz
Ana Paula
AP
Simões-Wüst
Shida
S
Yousefi
Hans-Uwe
HU
Simon
Rolf
R
Stahel
Uwe
U
Zangemeister-Wittke
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018288:Carcinoma, Small Cell / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division; D002945:Cisplatin / Q000494:pharmacology*; D004789:Enzyme Activation; D016195:G2 Phase; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism* / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D000077022:Survivin; D015854:Up-Regulation
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; D002945:Cisplatin