PT  - JOURNAL ARTICLE
AU  - Lin, Yidan
AU  - Liu, Xiangguo
AU  - Yue, Ping
AU  - Benbrook, Doris M.
AU  - Berlin, K. Darrell
AU  - Khuri, Fadlo R.
AU  - Sun, Shi-Yong
TI  - Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells
AID  - 10.1158/1535-7163.MCT-08-0648
DP  - 2008 Nov 01
TA  - Molecular Cancer Therapeutics
PG  - 3556--3565
VI  - 7
IP  - 11
4099  - http://mct.aacrjournals.org/content/7/11/3556.short
4100  - http://mct.aacrjournals.org/content/7/11/3556.full
SO  - Mol Cancer Ther2008 Nov 01; 7
AB  - The flexible heteroarotinoid, SHetA2, is a novel compound with apoptosis-inducing and anticancer activities in vitro and in vivo. Our previous research showed that up-regulation of death receptor 5 plays a critical role in the mechanism of SHetA2-induced apoptosis in human lung cancer cells. The hypothesis of this study was that the mechanism of SHetA2-induced apoptosis requires modulation of additional proteins critical for regulation of apoptosis, including cellular FLICE-inhibitory protein (c-FLIP), survivin, X-linked inhibitor of apoptosis, Bcl-2, Bcl-XL, Bax, and Bim. Western blot analysis showed that c-FLIP and survivin were substantially reduced in all of the tested cell lines exposed to SHetA2 compared with other proteins that were reduced only in a subset of the cell lines tested. Strikingly, overexpression of c-FLIP, but not survivin, protected cells from SHetA2-induced apoptosis and enhancement of TRAIL-initiated apoptosis, although knockdown of endogenous survivin did slightly sensitize cells to SHetA2-induced apoptosis. Consistent with these results, small interfering RNA-mediated reduction of c-FLIP was more effective than survivin down-regulation in triggering apoptosis in these cell lines. SHetA2 increased ubiquitination of c-FLIP and the consequent degradation was abrogated by the proteasome inhibitor MG132. Although SHetA2 treatment led to increased c-Jun phosphorylation, the JNK inhibitor SP600125 did not prevent c-FLIP down-regulation by SHetA2. Thus, it appears that SHetA2 down-regulates c-FLIP levels by facilitating its ubiquitin/proteasome-mediated degradation independent of JNK activation. Collectively, the present study indicates that, in addition to death receptor 5 up-regulation, c-FLIP down-regulation is another important component of flexible heteroarotinoid (SHetA2)-induced apoptosis as well as enhancement of TRAIL-induced apoptosis. [Mol Cancer Ther 2008;7(11):1–10] [Mol Cancer Ther 2008;7(11):3556–65]