Broadening TRAIL's Targets

Abstract

Identifying agents that destroy tumor cells but leave normal cells unharmed is a major goal in developing effective cancer treatments. The cytokine TRAIL, a member of the tumor necrosis family, has shown such potential, as it preferentially induces apoptosis of cancer cells. Now, Kim et al. report a potential mechanism to expand the range of TRAIL cancer targets. Agonists for a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPARγ) sensitized tumor cells that are normally not responsive to TRAIL such that TRAIL did induce apoptosis. Although neither the PPARγ modulators nor TRAIL alone killed these tumor cells, combined treatment did. Furthermore, the combination did not kill normal cells. The mechanism appears not to involve PPARγ, because it persisted even in the presence of dominant-negative form of PPARγ. It seems to be mediated by the formation of a TRAIL receptor-associated signaling complex that activates the cell death program through caspase activation. A cytoplasmic protein called FLIP normally inhibits assembly of this complex, but PPARγ modulators somehow stimulate the degradation of FLIP through the ubiquitin-proteosome pathway. The cellular target of the PPARγ modulators that stimulates this proapoptotic effect has yet to be determined. Y. Kim, N. Suh, M. Sporn, J. C. Reed, An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. J. Biol. Chem. 277 , 22320-22329 (2002). [Abstract] [Full Text]