alpha-Lipoic acid prevents p53 degradation in colon cancer cells by blocking NF-kappa B induction of RPS6KA4
- Authors
- Yoo, Tae-Hyoung; Lee, Jin-Hee; Chun, Hyang-Sook; Chi, Sung-Gil
- Issue Date
- 7월-2013
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Keywords
- alpha-Lipoic acid; apoptosis; colon cancer; p53; RPS6KA4
- Citation
- ANTI-CANCER DRUGS, v.24, no.6, pp.555 - 565
- Indexed
- SCIE
SCOPUS
- Journal Title
- ANTI-CANCER DRUGS
- Volume
- 24
- Number
- 6
- Start Page
- 555
- End Page
- 565
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/102897
- DOI
- 10.1097/CAD.0b013e32836181eb
- ISSN
- 0959-4973
- Abstract
- alpha-Lipoic acid (alpha-LA) is a biogenic antioxidant that has been used successfully in the treatment of diabetic polyneuropathy and its application to many oxidative stress-associated chronic diseases has increased. In this study, we investigated the effect of alpha-LA on colorectal cancer cell growth and its underlying mechanism. alpha-LA treatment resulted in a marked reduction in the growth of HCT116 colon cancer cells in a dose-dependent manner through the G(1) arrest of the cell cycle and apoptosis induction. alpha-LA treatment significantly increased tumor cell response to various apoptotic stresses, such as etoposide, 5-fluorouracil, UVC, gamma-irradiation, hypoxia, and tumor necrosis factor alpha(TNF alpha). Interestingly, alpha-LA increased p53 protein stability and its apoptosis-enhancing effect was more evident in wild-type p53-carrying cells compared with p53-deficient cells, suggesting that the proapoptotic role of alpha-LA is associated with its p53-stabilizing function. On the basis of our microarray data showing alpha-LA downregulation of the ribosomal protein p90S6K (RPS6KA4), which has been reported to inhibit p53 function, we tested whether alpha-LA regulation of RPS6KA4 is associated with its proapoptotic function. alpha-LA treatment led to a marked reduction in the RPS6KA4 mRNA level in multiple colorectal cancer cells and restoration of RPS6KA4 expression markedly attenuated alpha-LA induction of apoptosis in a p53-dependent manner. In addition, we observed that RPS6KA4 expression is activated by TNF alpha whereas both basal and TNF alpha induction of RPS6KA4 are inhibited by the nuclear factor-kappa B (NF-kappa B) inhibitor BAY11-7082 or transfection of a dominant-negative mutant of NF-kappa B, indicating that NF-kappa B plays a crucial role in RPS6KA4 gene expression. Finally, we found that alpha-LA exerts an inhibitory effect on the nuclear translocation of NF-kappa B triggered by TNF alpha. Collectively, our study shows that alpha-LA suppresses colorectal tumor cell growth at least partially by preventing RPS6KA4-mediated p53 inhibition through blockade of NF-kappa B signaling. (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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