Understanding of tolerance in TRAIL-induced apoptosis and cancelation of its machinery by α-mangostin, a xanthone derivative
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Minami Kumazaki1, Haruka Shinohara1, Kohei Taniguchi1, Hiroshi Ueda1, Mayuko Nishi2, Akihide Ryo2, Yukihiro Akao1
1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido Gifu 501-1193, Japan
2Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0027, Japan
Minami Kumazaki, e-mail: [email protected]
Keywords: TRAIL-induced apoptosis, TRAIL-resistance, α-mangostin, miR-133b, cancer stem-like cell
Received: May 07, 2015 Accepted: July 03, 2015 Published: July 16, 2015
Tumor necrosis-factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-superfamily that selectively induces apoptosis through death receptors (DRs) 4 and/or 5 in cancer cells. These receptors are expressed on the cancer cell surface, without affecting normal cells. Unfortunately, many clinical studies have shown that cancer cells acquire TRAIL-resistance and finally avoid TRAIL-induced apoptosis. The detailed mechanisms of this resistance are not well understood. In the current study, we established a TRAIL-resistant human colon cancer DLD-1 cell line to clarify the mechanisms of TRAIL-resistance and developed agents to cancel its machinery. Also, we found that cancer stem-like cells from breast epithelial proliferating MCF10A cells were also sensitive to TRAIL-induced apoptosis. The enforced expression of DR5 in both TRAIL-resistant cells partially recovered the sensitivity to the TRAIL ligand, which was judged by the activation of caspase-8. As a result, we newly found that the mechanisms of TRAIL-resistance comprised co-existence of a decrease in the expression level of DR5 along with malfunction of its recruitment to the cell surface, as evidenced by Western blot and immunocytological analysis, respectively. Interestingly, α-mangostin, which is a xanthone derivative, canceled the resistance by increasing the expression level of DR5 through down-regulation of miR-133b and effectively induced the translocation of DR5 to the cancer cell surface membrane in TRAIL-resistant DLD-1 cells. These findings indicate that α-mangostin functioned as a sensitizer of TRAIL-induced apoptosis and may thus serve as a possible adjuvant compound for cytokine therapy to conquer TRAIL-resistance.
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