alpha-TEA cooperates with MEK or mTOR inhibitors to induce apoptosis via targeting IRS/PI3K pathways

作者：Tiwary R; Yu W; Sanders B G; Kline K^*

来源：British Journal of Cancer, 2011, 104(1): 101-109.

DOI：10.1038/sj.bjc.6606019

• alpha-TEA
• Akt
• breast cancer
• ERK
• IRS-1
• mTOR

BACKGROUND: alpha-Tocopherol ether-linked acetic acid (alpha-TEA) is a promising agent for cancer prevention/therapy based on its antitumour actions in a variety of cancers.
METHODS: Human breast cancer cells, MCF-7 and HCC-1954, were used to study the effect of alpha-TEA using Annexin V/PI staining, western blot analyses, and siRNA knockdown techniques.
RESULTS: alpha-Tocopherol ether-linked acetic acid suppressed constitutively active basal levels of pAKT, pERK, pmTOR, and their downstream targets, as well as induced both cell types to undergo apoptosis. Phosphoinositide 3-kinase (PI3K) inhibitor wortmannin suppressed pAKT, pERK, pmTOR, and their downstream targets, indicating PI3K to be a common upstream mediator. In addition, alpha-TEA induced increased levels of pIRS-1 (Ser-307), a phosphorylation site correlated with insulin receptor substrate-1 (IRS-1) inactivation, and decreased levels of total IRS-1. Small interfering RNA (siRNA) knockdown of JNK blocked the impact of alpha-TEA on pIRS-1 and total IRS-1 and impeded its ability to downregulate the phosphorylated status of AKT, ERK, and mTOR. Combinations of alpha-TEA + MEK or mTOR inhibitor acted cooperatively to induce apoptosis and reduce basal levels of pERK and pmTOR. Importantly, inhibition of MEK and mTOR resulted in increased levels of pAKT and IRS-1, and alpha-TEA blocked them.
CONCLUSIONS: Downregulation of IRS-1/PI3K pathways via JNK are critical for alpha-TEA and alpha-TEA + MEK or mTOR inhibitor-induced apoptosis in human MCF-7 and HCC-1954 breast cancer cells. British Journal of Cancer (2011) 104, 101-109. doi:10.1038/sj.bjc.6606019 www.bjcancer.

• 出版日期2011-1-4