Id1, inhibitor of differentiation, is a key protein mediating anti-tumor responses of gamma-tocotrienol in breast cancer cells

Wei Ney Yap^a,1, Norazean Zaiden^a,1, Yee Ling Tan^b, Chang Piek Ngoh^c, Xue Wu Zhang^d, Y.C. Wong,^e, M.T. Ling ^f,* and Yee Leng Yap^a,*
^aDavos Life Science Pte. Ltd., Cancer Research Laboratory, 16 Tuas South Street 5, Singapore
^bSingapore Bioimaging Consortium (SBIC), Biomedical Sciences Institutes, 11 Biopolis Way #02-02 Helios, Singapore 138667, Singapore
^cDuke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore
^dCollege of Light Industry and Food Sciences, South China University of Technology, Guang Zhou, China
^eDepartment of Anatomy, Cancer Biology Lab, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, Laboratory Block, 21 Sassoon Road, Hong Kong SAR, China
^fAustralian Prostate Cancer Research Centre-Queensland Institute of Health and Biomedical Innovation (IHBI), QUT, Australia

Cancer Letters 291 (2010) 187–199
doi:10.1016/j.canlet.2009.10.012
2009 Elsevier Ireland Ltd.
0304-3835/$
Article Accepted on: 15 October 2009

Abstract:

Gamma-tocotrienol has demonstrated anti-proliferative effect on breast cancer (BCa) cells, but mechanisms involved are largely unknown. This study aimed at deciphering the molecular pathways responsible for its activity. Our results showed that treatment of BCa cells with gamma-tocotrienol resulted in induction of apoptosis as evidenced by activation of pro-caspases, accumulation of sub-G1 cells and DNA fragmentations. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of Id1 and NF-jB through modulation of their upstream regulators (Src, Smad1/5/8, Fak and LOX). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK signaling pathway and inhibition of JNK activity by specific inhibitor partially blocked the effect of gamma-tocotrienol. Furthermore, synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Interestingly, in cells that treated with gamma-tocotrienol, alpha-tocopherol or b-aminoproprionitrile were found to partially restore Id1 expression. Meanwhile, this restoration of Id1 was found to protect the cells from gamma-tocotrienol induced apoptosis. Consistent outcome was observed in cells ectopically transfected with the Id-1 gene. Our results suggested that the anti-proliferative and chemosensitization effect of gamma-tocotrienol on BCa cells may be mediated through downregulation of Id1 protein.

Keywords:

Tocotrienol, Tocopherol, Vitamin E, Breast cancer, Id-1, Docetaxel, Chemosensatizing