RRR-alpha-tocopherol succinate down-regulates oncogenic Ras signaling

Molecular Cancer Therapeutics
Sreenivasa DonapatyMokenge P Malafa

Abstract

alpha-Tocopherol succinate (TS), an analogue of vitamin E, has growth-inhibitory activity in a wide spectrum of in vitro and in vivo cancer models. Here, we report that modulation of oncogenic Ras is associated with TS activity. TS inhibits the proliferation and induces apoptosis of NIH3T3 cells stably transfected with oncogenic K-Ras and H-Ras, but not NIH3T3 cells expressing empty vector. TS treatment resulted in decreased Ras protein levels in oncogenic Ras expressing NIH3T3 cells but not in parental NIH3T3 cells. Treatment with TS suppressed the levels of phospho-Akt and phospho-Erk1/2 in oncogenic Ras expressing NIH3T3 cells. Overexpression of constitutively active phosphoinositide-3-kinase, Akt, and Mek1/2 significantly attenuated TS growth inhibition of oncogenic Ras-transformed NIH3T3 mouse fibroblast cell lines. In addition, transcriptional targets of oncogenic Ras such as c-Myc, cyclin D1, and E2F1 were down-regulated by TS in oncogenic Ras-expressing cells. The above TS effects on oncogenic Ras signaling were also observed in endogenous oncogenic K-Ras expressing HCT 116 (human colon cancer) and MDA-MB-231 (human breast cancer) cells. Taken together, these data show that TS down-regulation of the Ras signaling pathwa...Continue Reading

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