Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells.

Abstract

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-X(L), 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.

• Authors: Yidan Lin, Xiangguo Liu, Ping Yue, Doris M Benbrook, K Darrell Berlin, Fadlo R Khuri, Shi-Yong Sun
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 11 Pg. 3556-65 (Nov 2008) ISSN: 1535-7163 [Print] United States
• PMID: 19001438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• (((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione
• Antineoplastic Agents
• BIRC5 protein, human
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Chromans
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Survivin
• TNF-Related Apoptosis-Inducing Ligand
• Thiones

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
• Cell Line, Tumor
• Chromans (pharmacology)
• Down-Regulation
• Gene Silencing
• Humans
• Inhibitor of Apoptosis Proteins
• Lung Neoplasms (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Survivin
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Thiones (pharmacology)