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Heat shock protein 70 suppresses PS‐341‐induced apoptosis via inhibition of JNK pathway independently of Akt activation in lung cancer cells
Author(s) -
Lee KyoungHee,
Lee ChoonTaek,
Kim Young Whan,
Han Sung Koo,
Shim YoungSoo,
Yoo ChulGyu
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a122
Subject(s) - protein kinase b , apoptosis , pi3k/akt/mtor pathway , hsp70 , phosphorylation , microbiology and biotechnology , chemistry , cancer research , proteasome inhibitor , signal transduction , heat shock protein , biology , biochemistry , gene
PS‐341 is a highly selective and potent proteasome inhibitor, which was found to induce apoptosis via activation of JNK‐caspase pathway. Although proteasome inhibitor has been known to up‐regulate hsp70, which can protect cells against many cellular stresses, its role in PS‐341‐induced apoptosis and its relationship with PI3K/Akt is not known. This study was undertaken to elucidate the role of hsp70 in PS‐341‐induced apoptosis in lung cancer cells. Adenovirus‐mediated overexpression of hsp70 suppressed PS‐341‐induced JNK activation and apoptosis. PS‐341 up‐regulated hsp70 expression in NCI‐H157 and A549 cells in a time and dose‐dependent manner. When this up‐regulation was blocked by adenovirus vectors expressing hsp70 antisense RNA, JNK‐dependent apoptosis by PS‐341 was enhanced. Hsp70 was found to be associated physically with JNK1 in immunoprecipitation assay. PS‐341 induced PI3K/Akt‐dependent GSK‐3β phosphorylation on serine 9 (p‐GSK‐3β ), and it negatively regulated PS‐341‐induced JNK activation and apoptosis. Blocking Akt activation or increase in p‐GSK‐3β suppressed heat‐shock‐induced up‐regulation of hsp70 expression, but it did not affect up‐regulation of hsp70 by PS‐341. Moreover, suppression of JNK activation by hsp70 overexpression was not reversed by blocking Akt activation. Taken together, PS‐341‐induced apoptosis is negatively regulated by up‐regulating hsp70 expression via suppression of JNK activation independently of Akt activation in lung cancer cells.