Tumor suppressor p73 transcriptionally regulatesc-FLIPto impede its priming of extrinsic apoptosis while a “switcher compound” degrades c-FLIP protein

Abstract

AbstractThe tumor suppressor p73 is a member of the p53 family, and transcriptionally activates multiple p53-targets involved in cell cycle regulation and apoptosis. In addition to pro-apoptotic signaling, outcomes of p73 activation include cell survival signals. Thus, p73 activity and targets may provide insight in cell fate outcomes between cell survival and apoptosis following cellular stress. We report thatcellular FLICE inhibitory protein(c-FLIP), a master antiapoptotic factor, is a transcriptional target of p73. The activation of p73 (α and β isoforms) transcriptionally upregulatesc-FLIP-L/Sexpression in cancer cells. The cell fate decision following p73 activation is determined by the adjustment of the balance of outcomes of p73 activation between p73-induced pro-apoptotic signaling andc-FLIP-L/Sexpression in cancer cells. p73 primes extrinsic apoptosis via an autocrine death ligand-DR5 axis, and the priming appears to be titrated at the level of c-FLIP-L/S. The p73-upregulation ofc-FLIP-L/Sincreases the threshold of extrinsic apoptosis. Cells with poor priming levels convert to cell cycle arrest and survival. Depletion ofc-FLIP-L/Sincreases the p73-priming levels towards extrinsic apoptosis and sensitizes cancer cells to p73-primed extrinsic apoptosis. We further identified a small-molecule CB-7587351 (“switcher compound”) that alters p73 activation outcomes through c-FLIP-L/S protein degradation. Therapeutic activation of p73 can restore p53-signaling in mutant p53-expressing cancer cells effectively bypassing the p53 deficiency in cancer cells. Our discovery of p73 transcriptional upregulation of c-FLIP provides a promising strategy for depleting c-FLIP to improve antitumor efficacy of p73-targeting cancer therapy for p53-mutant tumors.