期刊
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE
卷 93, 期 4, 页码 306-320出版社
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/bcb-2014-0123
关键词
gamma-tocotrienol; autophagy; breast cancer; endoplasmic reticulum stress; apoptosis
资金
- First Tec International Ltd. (Hong Kong)
- Malaysian Palm Oil Council (MPOC)
- Louisiana Cancer Foundation
- Louisiana Campuses Research Initiative (LACRI)
The anticancer effects of gamma-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 mu mol/L of gamma-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. gamma-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of gamma-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in gamma-tocotrienol-induced cytotoxicity. gamma-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2 alpha, Bip, IRE1 alpha, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that gamma-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.
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