Anti-tumor actions of vitamin E analog [alpha]-TEA alone and in combinations in human breast cancer cells
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Breast cancer is the second leading cause of mortality among women in the US. A contributing factor to such dire statistics is that conventional therapies are all too often compromised due to tumor relapse. Clearly there is an urgent need for agents that can circumvent resistance when combined with conventional therapies. RRR-α-tocopherol ether-linked acetic acid analog (α-TEA), a small bioactive lipid, exhibits in vitro and in vivo anticancer actions in a variety of cancers, including breast, prostate, and ovarian with little or no effect on normal cells and tissues, which potentially makes it an ideal chemotherapeutic agent. My studies investigated the anticancer actions of α-TEA alone and in combination with therapeutic agents using human breast cancer cell lines. Data show that: (i) Endoplasmic reticulum (ER) stress plays an important role in α-TEA induced apoptosis by enhancing DR5/caspase-8 pro-apoptotic signaling and suppressing anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling, (ii) α-TEA plus tamoxifen act cooperatively to circumvent acquired and de novo tamoxifen resistance, resulting in cancer cell death by apoptosis. Mechanistically, the circumvention of tamoxifen resistance involved induction of DR5/caspase-8 pro-apoptotic mediators and suppression of anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling. (iii) α-TEA alone or with tamoxifen circumvents tamoxifen resistance via disruption of membrane cholesterol rich lipid raft microdomains. Cholesterol blocked the ability of α-TEA + tamoxifen to circumvent tamoxifen resistance. (iv) α-TEA in combination with PI3K, MEK or mTOR inhibitors acted cooperatively to induce apoptosis, by down-regulation of IRS-1/PI3K mediators via JNK. (v) α-TEA plus doxorubicin or cisplatin enhanced apoptosis in p53 mutant human breast cancer cells via targeting p53-inducible genes in a p73-dependent manner; namely, via up-regulation of death receptor-5 (DR5), CD95/APO-1 (Fas), Bax and Noxa, as well as down-regulation of anti-apoptotic mediator Bcl-2. Data showed that p73 responses were downstream of c-Abl, JNK and Yap. (vi) FASN inhibitor alone or with Tamoxifen or α-TEA circumvents tamoxifen resistance, thereby, providing novel strategies for restoring tamoxifen sensitivity to tamoxifen resistant cancers. In summary data show, α-TEA alone and in combination with multiple clinically-relevant anticancer agents is a promising anticancer agent.