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Understanding of tolerance in TRAIL-induced apoptosis and cancelation of its machinery by ?-mangostin, a xanthone derivative.

ABSTRACT: 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, ?-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 ?-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.

SUBMITTER: Kumazaki M

PROVIDER: S-EPMC4694869 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Understanding of tolerance in TRAIL-induced apoptosis and cancelation of its machinery by α-mangostin, a xanthone derivative.

Kumazaki Minami M Shinohara Haruka H Taniguchi Kohei K Ueda Hiroshi H Nishi Mayuko M Ryo Akihide A Akao Yukihiro Y

Oncotarget 20150901 28

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 cur ...[more]

PMID: 26304927

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Project description:The relevance of the adaptor protein TNF receptor-associated factor 2 (TRAF2) for signal transduction of the death receptor tumour necrosis factor receptor1 (TNFR1) is well-established. The role of TRAF2 for signalling by CD95 and the TNF-related apoptosis inducing ligand (TRAIL) DRs, however, is only poorly understood. Here, we observed that knockdown (KD) of TRAF2 sensitised keratinocytes for TRAIL- and CD95L-induced apoptosis. Interestingly, while cell death was fully blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) in control cells, TRAF2-depleted keratinocytes were only partly rescued from TRAIL- and CD95L-induced cell death. In line with the idea the only partially protective effect of zVAD-fmk on TRAIL- and CD95L-treated TRAF2-depleted keratinocytes is due to the induction of necroptosis, combined treatment with zVAD-fmk and the receptor interacting protein 1 (RIP1) inhibitor necrostatin-1 [corrected] fully rescued these cells. To better understand the impact of TRAF2 levels on RIP1- and RIP3-dependent necroptosis and RIP3-independent apoptosis, we performed experiments in HeLa cells that lack endogenous RIP3 and HeLa cells stably transfected with RIP3. HeLa cells, in which necroptosis has no role, were markedly sensitised to TRAIL-induced caspase-dependent apoptosis by TRAF2 KD. In RIP3-expressing HeLa transfectants, however, KD of TRAF2 also strongly sensitised for TRAIL-induced necroptosis. Noteworthy, priming of keratinocytes with soluble TWEAK, which depletes the cytosolic pool of TRAF2-containing protein complexes, resulted in strong sensitisation for TRAIL-induced necroptosis but had only a very limited effect on TRAIL-induced apoptosis. The necroptotic TRAIL response was not dependent on endogenously produced TNF and TNFR signalling, since blocking TNF by TNFR2-Fc or anti-TNFα had no effect on necroptosis induction. Taken together, we identified TRAF2 not only as a negative regulator of DR-induced apoptosis but in particular also as an antagonist of TRAIL- and CD95L-induced necroptosis.

Dataset Information

Understanding of tolerance in TRAIL-induced apoptosis and cancelation of its machinery by ?-mangostin, a xanthone derivative.

Publications

Understanding of tolerance in TRAIL-induced apoptosis and cancelation of its machinery by α-mangostin, a xanthone derivative.

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