Id1, inhibitor of differentiation, is a key protein mediating anti-tumor responses of gamma-tocotrienol in breast cancer cells.
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-kappaB 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 beta-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.
Yap
Wei Ney
WN
Davos Life Science Pte. Ltd., Cancer Research Laboratory, 16 Tuas South Street 5, Singapore. weiney.yap@davoslife.com <weiney.yap@davoslife.com>
Zaiden
Norazean
N
Tan
Yee Ling
YL
Ngoh
Chang Piek
CP
Zhang
Xue Wu
XW
Wong
Y C
YC
Ling
M T
MT
Yap
Yee Leng
YL
D000728:Androgens / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003094:Collagen; D053938:DNA Fragmentation; D015536:Down-Regulation; D004338:Drug Combinations; D004967:Estrogens / Q000502:physiology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism; D007797:Laminin; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011509:Proteoglycans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000728:Androgens; D002839:Chromans; D004338:Drug Combinations; D004967:Estrogens; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D014810:Vitamin E; C013649:plastochromanol 8; D003094:Collagen