Involvement of PI3K-AKT-mTOR pathway in protein kinase CKII inhibition-mediated senescence in human colon cancer cells

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• 作者：Ji Hye Park ; Jin Joo Kim ; Young-Seuk Bae ; ^{ysbae@knu.ac.kr}
• 关键词：CKII ; protein kinase CKII (also known as casein kinase II) ; DMEM ; Dulbecco&rsquo ; s modified Eagle&rsquo ; s medium ; DHE ; dihydroethidium ; DRB ; 5 ; 6-dichloro-1-¦Ã-d-ribofuranosylbenzimidazole ; ETH ; ethidium ; FBS ; fetal bovine serum ; HA ; hemagglutinin ; mTOR ; m
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2013
• 出版时间：19 April, 2013
• 年：2013
• 卷：433
• 期：4
• 页码：420-425
• 全文大小：1182 K

文摘

Cellular senescence is a tumor suppression mechanism. We previously reported that CKII downregulation induces senescence in human lung fibroblast IMR-90 and colon cancer HCT116 cells. In this study, potential longevity drugs, including rapamycin, vitamin C, and vitamin E, blocked CKII downregulation-mediated senescence through reduction of reactive oxygen species (ROS) production in HCT116 cells. Since rapamycin is a mammalian target of rapamycin (mTOR) inhibitor, we examined the roles of mTOR and its upstream regulators phosphatidylinositol 3-kinase (PI3K) and AKT in CKII inhibition-mediated senescence. CKII¦Á knock-down or CKII inhibitor treatment strikingly increased phosphorylation of mTOR, p70S6K, an mTOR substrate, and AKT, whereas CKII¦Á overexpression reduced this phosphorylation event. This result indicated that CKII inhibition activated the PI3K-AKT-mTOR pathway. Further, pharmacological inhibition of PI3K and AKT attenuated ROS production and senescence in CKII-downregulated cells. Taken together, these results demonstrate, for the first time, that the PI3K-AKT-mTOR-ROS pathway is necessary for CKII inhibition-mediated cellular senescence.