Abstract 4351: Gamma-tocotrienol not alpha-tocopherol is cytotoxic to prostate cancer cells through modulation of phospho-c-Jun and phospho-Erk.
Authors: Mahboob Rashid , Ramsauer Victoria P. , Lightner Janet W. , Stone William L. , Krishnan Koyamangalath 
Published: August 2014

Abstract
Chemical differences in gamma-tocotrienol including the presence of an isoprenoid side chain are responsible for differences in cytotoxic potency of gamma-tocotrienol compared to alpha-tocopherol. Alpha-tocopherol has been shown to be ineffective in prostate cancer chemoprevention in the SELECT trial; in fact, there was an increased incidence of prostate cancer in the alpha-tocopherol arm indicative of deleterious effects. Therefore, we explored the cytotoxic effects of alpha-tocopherol (AT), gamma-tocopherol (GT) and gamma-tocotrienol (GT3) in prostate cancer cell lines, PC-3 (androgen independent) and LNCaP (androgen dependent). Prostate cancer cell lines were grown in culture and treated with various concentrations and duration with the vitamin E isoforms. Cytotoxicity was determined by MTT and cell viability assays. We also explored possible molecular mechanisms to further understand differences in effects between the tocopherols and tocotrienols.
GT3 showed cytotoxic effects in a dose and time-dependent manner, in both cell lines. PC-3 cells were noted to be more sensitive to growth suppression effects of GT3 than LNCaP cells. GT did not show significant cytotoxicity on cell growth at any given dose or time end point, whereas AT may promote prostate cancer cell growth. We also found that the combination of AT (40um) with increasing dose concentration of GT3 showed less pronounced cytotoxicity at 24 hours, when compared with various concentrations of GT3 alone, again suggesting a possible antagonistic role of AT.
Exposure of PC-3 and LNCaP cells to increasing dose of GT3 was also examined for p-AKT, p-Erk, p-ERBB2 and phospho-c-Jun activity via Western blot at various time points. Our results show a dose dependent up regulation of pc-Jun and p-Erk in GT3 treated cells. No effects were noted on p-Akt or p-ERBB2 at the time points and concentrations studied. Some earlier studies found JNK and MAPK/Erk activation as playing a central role in the tocopherol induced apoptosis. C-Jun is downstream effector in JNK signaling pathway, activates transcription factors, which in turn modulate gene expression, to generate appropriate biological responses leading to apoptosis. In contrast to Erk recognized role in cancer cells proliferation we found Erk 1/2 up-regulation in GT3 induced apoptosis. This finding has also been reported earlier in some studies on prostate and other cancer cell lines. Our work shows that GT3 has cytotoxic effects on prostate cancer cells and induces cellular apoptosis through the modulation of phospho-c-Jun and MAPK pathways, while AT has either none or promotes prostate cancer cell growth in culture. Further studies are under way to dissect the molecular mechanisms of c-Jun and Erk activation by gamma-tocotrienol in prostate cancer cells.
Citation Format: Rashid Mahboob, Victoria P. Ramsauer, Janet W. Lightner, William L. Stone, Koyamangalath Krishnan. Gamma-tocotrienol not alpha-tocopherol is cytotoxic to prostate cancer cells through modulation of phospho-c-Jun and phospho-Erk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4351. doi:10.1158/1538-7445.AM2013-4351