Chemical, physical and biological triggers of evolutionary conserved Bcl-xL-mediated apoptosis

Abstract

ABSTRACT The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. Here, we show that Bcl-xL-specific agent A-1155463 prematurely kills cells of different origins and the small roundworms ( C. elegans ), when combined with DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO). The synergistic effect of 4NQO-A-1155463 combination was p53-dependent, was associated with the release of Bad and Bax from Bcl-xL, which triggered mitochondrial outer membrane permeabilization (MOMP). Combinations of Bcl-xL-specific inhibitors with certain anticancer compounds or physical insults also killed cells. Collectively, our results suggest that biological, chemical and physical factors trigger evolutionary conserved Bcl-xL-mediated apoptotic pathway.