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Title: Autophagy-mediated degradation of IAPs and c-FLIP L potentiates apoptosis induced by combination of TRAIL and Chal-24

Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. In this paper, 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. In conclusion, 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.
 [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [3] ;  [3] ;  [4] ;  [4] ;  [5] ;  [6] ;  [5] ;  [1]
  1. Lovelace Respiratory Research Institute, Albuquerque, NM (United States)
  2. Lovelace Respiratory Research Institute, Albuquerque, NM (United States); Sichuan Univ., Chengdu (People's Republic of China)
  3. Chongqing Medical University, Chongqing (People's Republic of China)
  4. Sichuan Univ., Chengdu (People's Republic of China); Univ. of New Mexico and New Mexico VA Health Care System, Albuquerque, NM (United States)
  5. Sichuan Univ., Chengdu (People's Republic of China)
  6. Univ. of Minnesota, Minneapolis, MN (United States)
Publication Date:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Journal of Cellular Biochemistry
Additional Journal Information:
Journal Volume: 117; Journal Issue: 5; Journal ID: ISSN 0730-2312
Research Org:
Lovelace Respiratory Research Inst., Albuquerque, NM (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; TRAIL; CHAL-24; autophagy; apoptosis; c-IAP; c-FLIP
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1401400