The pseudo-caspase FLIP(L) regulates cell fate following p53 activation.

Autor:	Lees A; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., McIntyre AJ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Crawford NT; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Falcone F; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., McCann C; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Holohan C; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Quinn GP; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Roberts JZ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Sessler T; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Gallagher PF; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Gregg GMA; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., McAllister K; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., McLaughlin KM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Allen WL; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Egan LJ; Discipline of Pharmacology & Therapeutics, Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland., Ryan AE; Discipline of Pharmacology & Therapeutics, Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.; Regenerative Medicine Institute, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland., Labonte-Wilson MJ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Dunne PD; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Wappett M; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Coyle VM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Johnston PG; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Kerr EM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom., Longley DB; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom; d.longley@qub.ac.uk S.McDade@qub.ac.uk., McDade SS; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland BT9 7BL, United Kingdom; d.longley@qub.ac.uk S.McDade@qub.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jul 28; Vol. 117 (30), pp. 17808-17819. Date of Electronic Publication: 2020 Jul 13.
DOI:	10.1073/pnas.2001520117
Abstrakt:	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 combination 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 expression 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 induced 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 apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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