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

Sreenivasa Donapaty1, Somaja Louis, Elizabeth Horvath

  • 1Gastrointestinal Tumor Program, Division of Gastrointestinal Tumors, Department of Interdisciplinary Oncology, University of South Florida, Tampa, Florida 33612, USA.

Molecular Cancer Therapeutics
|March 1, 2006
PubMed

Insights

Alpha-Tocopherol succinate (TS), a vitamin E analogue, inhibits cancer cell growth by down-regulating Ras signaling pathways. This suggests TS has potential as a chemopreventive and therapeutic agent for Ras-dependent tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Alpha-Tocopherol succinate (TS), a vitamin E analogue, exhibits anti-cancer properties in various models.
  • Oncogenic Ras signaling pathways are frequently activated in cancer and drive tumor growth and survival.

Purpose of the Study:

  • To investigate the role of oncogenic Ras modulation in the anti-cancer activity of TS.
  • To elucidate the specific signaling pathways targeted by TS in Ras-transformed cells.

Main Methods:

  • Utilized NIH3T3 cell lines engineered to express oncogenic K-Ras or H-Ras.
  • Assessed the effects of TS on cell proliferation, apoptosis, protein levels (Ras, phospho-Akt, phospho-Erk1/2), and transcriptional targets (c-Myc, cyclin D1, E2F1).
  • Examined TS activity in endogenous oncogenic Ras-expressing human cancer cell lines (HCT 116, MDA-MB-231).

Main Results:

  • TS inhibited proliferation and induced apoptosis in Ras-transformed cells, but not in control cells.
  • TS treatment decreased Ras protein levels and suppressed phospho-Akt and phospho-Erk1/2 signaling in oncogenic Ras-expressing cells.
  • TS down-regulated key Ras transcriptional targets and demonstrated similar effects in human colon and breast cancer cells.

Conclusions:

  • TS exerts its anti-cancer effects, at least in part, by down-regulating Ras signaling pathways, including Mek/Erk and phosphoinositide-3-kinase/Akt.
  • These findings support the investigation of TS for chemoprevention and therapy in Ras-dependent cancers.
  • Phospho-Erk and phospho-Akt may serve as biomarkers for TS activity.

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