Autophagy-Mediated Degradation of IAPs and c-FLIPL Potentiates Apoptosis Induced by Combination of TRAIL and Chal-24

Jennings Xu, Xiuling Xu, Shaoqing Shi, Qiong Wang, Bryanna Saxton, Weiyang He, Xin Gou, Jun Ho Jang, Toru Nyunoya, Xia Wang, Chengguo Xing, Lin Zhang, Yong Lin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. Here we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIPL) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIPL and c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by Chal-24 and TRAIL combination, which was associated with attenuation of c-FLIPL and c-IAPs degradation. Altogether, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIPL and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.

Original languageEnglish (US)
Pages (from-to)1136-1144
Number of pages9
JournalJournal of Cellular Biochemistry
Volume117
Issue number5
DOIs
StatePublished - May 1 2016

Bibliographical note

Publisher Copyright:
© 2015 Wiley Periodicals, Inc.

Keywords

  • APOPTOSIS
  • AUTOPHAGY
  • CHAL-24
  • TRAIL
  • c-FLIP
  • c-IAP

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