Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling
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Tocotrienols are naturally occurring forms of vitamin E based on their structural similarity. This study focused on investigating anticancer effects of tocotrienols and the mechanisms of apoptosis induction by tocotrienols in vivo and in vitro. Dietary delivery of γ-tocotrienol (γ-T3) suppressed tumor growth in a syngeneic implantation mouse mammary cancer model by inhibiting cell proliferation and inducing apoptosis. In cell culture studies, γ-T3 inhibited colony formation of a mouse mammary cancer cell line and human breast cancer cell lines. The anti-proliferative effects of tocotrienols were highly correlated with an increase in apoptosis based on Annexin V assessment. Treatment of human MDA-MB-231 and MCF-7 cells with γ-T3 induced cleavages of PARP as well as caspase-8, -9, and -3. Additional analyses showed that γ-T3 activated c-Jun NH2-terminal kinase (JNK) and p38 MAPK, and upregulated death receptor 5 (DR5) and C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress marker. Silencing either JNK or p38 MAPK reduced the increase in DR5 and CHOP and partially blocked γ-T3-induced apoptosis. Both DR5 and CHOP upregulation were required for γ-T3-induced apoptosis, and DR5 was transcriptionally regulated by CHOP after γ-T3 treatment. Moreover, γ-T3 increased the level of other ER-stress markers. Taken together, these results suggest that upregulation of DR5 by γ-T3 treatment is dependent on JNK and p38 MAPK activation which is mediated by ER-stress.
KeywordsTocotrienols Apoptosis Breast cancer 66cl-4 mouse mammary tumor model Endoplasmic reticulum stress Death receptor 5 C/EBP homologous protein
This research was supported by the Clayton Foundation for Research and the National Institute of Environmental Health Sciences Center Grant ES007784.
- 15.Shah JS, Sylvester PW (2005) Gamma-tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor κB activity. Exp Biol Med (Maywood) 230:235–241Google Scholar
- 16.Shun MC, Yu W, Gapor A, Parsons R, Atkinson J, Sanders BG, Kline K (2004) Pro-apoptotic mechanisms of action of a novel vitamin E analog (α-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells. Nutr Cancer 48(1):95–105CrossRefPubMedGoogle Scholar
- 17.Elangovan S, Hsieh TC, Wu JM (2008) Growth inhibition of human MDA-MB-231 breast cancer cells by delta-tocotrienol is associated with loss of cyclin D1/CDK4 expression and accompanying changes in the state of phosphorylation of the retinoblastoma tumor suppressor gene product. Anticancer Res 28(5A):2641–2647PubMedGoogle Scholar
- 19.McAnally JA, Gupta J, Sodhani S, Bravo L, Mo H (2007) Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. Exp Biol Med (Maywood) 232(4):523–531Google Scholar
- 30.Lawson KA, Anderson K, Simmons-Menchaca M, Atkinson J, Sun L, Sanders BG, Kline K (2004) Comparison of vitamin E derivatives of α-TEA and VES in reduction of mouse mammary tumor burden and metastasis. Exp Biol Med (Maywood) 229:954–963Google Scholar
- 32.Subcommittee on laboratory animal nutrition, committee on animal nutrition, board on agriculture, and national research council (1995) Nutrient requirements of laboratory animals (4th revised edition). National Academy Press, Washington, DCGoogle Scholar
- 52.Shah S, Sylvester PW (2004) Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary cancer cells. Exp Biol Med (Maywood) 229:745–755Google Scholar