Peer-Reviewed Journal Details
Mandatory Fields
Lees, A,McIntyre, AJ,Crawford, NT,Falcone, F,McCann, C,Holohan, C,Quinn, GP,Roberts, JZ,Sessler, T,Gallagher, PF,Gregg, GMA,McAllister, K,McLaughlin, KM,Allen, WL,Egan, LJ,Ryan, AE,Labonte-Wilson, MJ,Dunne, PD,Wappett, M,Coyle, VM,Johnston, PG,Kerr, EM,Longley, DB,McDade, SS
2020
July
Proceedings Of The National Academy Of Sciences Of The United States Of America
The pseudo-caspase FLIP(L) regulates cell fate following p53 activation
Published
Optional Fields
p53 apoptosis FLIP TRAIL-R2 entinostat NF-KAPPA-B DNA-BINDING C-FLIP CANCER ACETYLATION GENE APOPTOSIS EXPRESSION DEATH PUMA
117
17808
17819
p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combi-nation of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting ex-pression of FLIP(L) using siRNA or entinostat (a clinically relevant class -I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly in-duced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced ap-optosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.
10.1073/pnas.2001520117
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