Ability of α-TEA, alone or in combination with selenium, to induce human prostate cancer cells to undergo apoptosis via enhancement of pro-apoptotic Fas signaling and suppression of pro-life Akt signaling pathways
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In the present study, the anti-tumor efficacy of α-TEA, a derivative of RRR-α-tocopherol, was investigated in LNCaP and PC-3-GFP human prostate cancer cells. Data show that α-TEA induced apoptosis in both cell lines in a time- and dose-dependent manner. Data show that α-TEA induces apoptosis through the activation of pro-apoptotic Fas signaling and inhibition of pro-survival Akt signaling pathways. The role of FADD and Daxx in α-TEA-induced apoptosis was determined. Data show that α-TEA promotes the association of FADD with Fas. FADD siRNA significantly reduced α-TEA-induced apoptosis in LNCaP cells. However, in PC-3-GFP cells, FADD siRNA caused apoptosis in the absence of α-TEA, and in the presence of FADD siRNA, α-TEA-induced apoptosis was significantly enhanced, indicating pro-survival activity of FADD in PC-3-GFP cells. Although α-TEA did not change the total protein levels of Daxx, it did promote the association of Daxx with Fas. α-TEA-induced apoptosis was significantly reduced by Daxx siRNA, and enhanced by overexpression of wild type Daxx, showing the pro-apoptotic role of Daxx in α-TEA-induced apoptosis. α-TEA inhibited phosphorylation of all three Akt isoforms; namely, Akt1, Akt2, and Akt3, thereby removed the phosphorylation inhibition on FOXO1 and FOXO1-mediated upregulation of FasL enhanced apoptosis through Fas signaling pathway. Studies have shown that selenium is of value in prostate cancer prevention. Here we document that methylseleninic acid (MSA) acts synergistically with α-TEA to induce apoptosis in LNCaP and PC-3-GFP human prostate cancer celld in culture. Western blot analyses indicate the involvement of caspases-8, -9, and -3, as well as Akt, in the synergistic effect of α-TEA and MSA. In a preclinical PC-3-GFP xenograft mouse model, α-TEA and MSC separately and together significantly reduced tumor burden and metastatic lesions in lungs and lymph nodes. However, synergism with the combination that in cell culture were not obtained in the animal study. α-TEA alone was as effective as, perhaps better than, the combination treatment in ruducing tumor burden and inhibiting metastases. Thus, data support α-TEA alone, rather than α-TEA plus selenium, as a treatment for human prostate cancer.