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Akt1 inhibition by RNA interference sensitizes human non‐small cell lung cancer cells to cisplatin
Author(s) -
Lee Myoung Woo,
Kim Dae Seong,
Min Na Young,
Kim Heung Tae
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23371
Subject(s) - cisplatin , protein kinase b , mapk/erk pathway , akt1 , apoptosis , cancer research , transfection , rna interference , cancer cell , small interfering rna , cytotoxicity , chemistry , cell growth , kinase , biology , cell culture , microbiology and biotechnology , cancer , medicine , in vitro , chemotherapy , biochemistry , rna , gene , genetics
Akt/protein kinase B signaling is very important for cancer cell survival and growth when cells are exposed to various apoptotic stimuli. Akt is constitutively activated in NSCLC cells and is a potential target for enhancing the cytotoxicity of chemotherapeutic agents in treatment of NSCLC. In our study, we investigated whether down‐regulating Akt1 using RNAi techniques can enhance sensitivity to cisplatin in NSCLC cells. An siRNA targeting Akt1 significantly decreased the protein level of Akt1 and the activity of ERK. Treatment of these cells with 20 μM cisplatin increased apoptotic cell death ∼2.6‐fold compared to cells transfected with a scrambled siRNA. While Akt activity was slightly reduced, ERK activity was greatly increased in cells treated with cisplatin alone. Pretreatment of these cells with the selective MEK inhibitor U0126 effectively reduced the level of cisplatin‐induced apoptosis. These results imply that cisplatin‐induced MEK/ERK activation appears to mediate apoptotic cell death, but that constitutively activated Akt1 and/or ERK pathway may mediate resistance to cisplatin in NSCLC cells. Taken together, our data demonstrate that down‐regulation of Akt1 using RNAi enhances the chemosensitivity of NSCLC cells to cisplatin. © 2008 Wiley‐Liss, Inc.