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dc.contributor.authorXie, Y.
dc.contributor.authorWang, L.
dc.contributor.authorKhan, M.A.
dc.contributor.authorHamburger, A.W.
dc.contributor.authorGuang, W.
dc.contributor.authorPassaniti, A.
dc.contributor.authorMunir, K.
dc.contributor.authorRoss, D.D.
dc.contributor.authorDean, M.
dc.contributor.authorHussain, A.
dc.date.accessioned2021-04-12T16:48:47Z
dc.date.available2021-04-12T16:48:47Z
dc.date.issued2021-02-05
dc.identifier.urihttp://hdl.handle.net/10713/15230
dc.description.abstractWe explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC. Copyright 2021 by the authors. Licensee MDPI, Basel, Switzerland.en_US
dc.description.sponsorshipFunding: The study was supported by grants from the Department of Veterans' Affairs Merit Review Award (I01 BX000545, for A.H.) and NIH (NCI) Program Project Grant (2P30CA134274-09).en_US
dc.description.urihttps://doi.org/10.3390/cancers13040633en_US
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofCancers
dc.subjectARATen_US
dc.subjectLysosomeen_US
dc.subjectMetforminen_US
dc.subjectPARP-1en_US
dc.subjectPoly(ADP-ribose) (PAR)en_US
dc.subjectProstate canceren_US
dc.titleMetformin and androgen receptor-axis-targeted (Arat) agents induce two parp-1-dependent cell death pathways in androgen-sensitive human prostate cancer cellsen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/cancers13040633


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