The BET bromodomain inhibitor, JQ1, facilitates c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 and c-Myc inhibitionReport as inadecuate




The BET bromodomain inhibitor, JQ1, facilitates c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 and c-Myc inhibition - Download this document for free, or read online. Document in PDF available to download.

Journal Title:

Oncotarget

Volume:

Volume 6, Number 33

Publisher:

Impact Journals | 2015-10-27, Pages 34669-34679

Type of Work:

Article | Final Publisher PDF

Abstract: Inhibition of BET bromodomains BRDs has emerged as a promising cancer therapeutic strategy. Accordingly, inhibitors of BRDs such as JQ1 have been actively developed and some have reached clinical testing. However, the mechanisms by which this group of inhibitors exerts their anticancer activity, including induction of apoptosis, have not been fully elucidated. This report reveals a previously uncovered activity of JQ1 in inducing c-FLIP degradation and enhancing TRAIL-induced apoptosis. JQ1 potently decreased c-FLIP both long and short forms levels in multiple cancer cell lines without apparently increasing the expression of DR5 and DR4. Consequently, JQ1, when combined with TRAIL, synergistically induced apoptosis; this enhanced apoptosis-inducing activity could be abolished by enforced expression of ectopic FLIPL or FLIPS. Hence it appears that JQ1 decreases c-FLIP levels, resulting in enhancement of TRAIL-induced apoptosis. Inhibition of proteasome with MG132 prevented JQ1-induced c-FLIP reduction. Moreover, JQ1 decreased c-FLIP stability. Therefore, JQ1 apparently decreases c-FLIP levels through facilitating its proteasomal degradation. Genetic inhibition of either BRD4 or c-Myc by knocking down their expression failed to mimic JQ1 in decreasing c-FLIP and enhancing TRAIL-induced apoptosis, suggesting that JQ1 induces c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 or c-Myc inhibition. In summary, our findings in this study highlights a novel biological function of JQ1 in modulating apoptosis and warrant further study of the potential treatment of cancer with the JQ1 and TRAIL combination.

Subjects: Health Sciences, Oncology - Biology, Cell - Research Funding: This study was supported by the Emory Winship Cancer Institute Halpern Research Scholar award to SYS.

Keywords: Science and Technology - Life Sciences and Biomedicine - Oncology - Cell Biology - JQ1 - c-FLIP - TRAIL - apoptosis - BRD4 - c-Myc - LUNG-CANCER CELLS - CELECOXIB-INDUCED APOPTOSIS - DOWN-REGULATION CONTRIBUTES - THERAPEUTIC STRATEGY - LEUKEMIA-CELLS - PROTEIN - INDUCTION - DEATH - OSTEOSARCOMA - SENSITIVITY -



Author: Weilong Yao, Ping Yue, Fadlo Khuri, Shi-Yong Sun,

Source: https://open.library.emory.edu/



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