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dc.contributor.authorLim, Syer C
dc.contributor.authorJansson, Patric J
dc.contributor.authorAssinder, Stephen J
dc.contributor.authorMaleki, Sanaz
dc.contributor.authorRichardson, Des R
dc.contributor.authorKovacevic, Zaklina
dc.date.accessioned2020-11-09T04:14:46Z
dc.date.available2020-11-09T04:14:46Z
dc.date.issued2020
dc.identifier.issn0892-6638en_US
dc.identifier.doi10.1096/fj.201903167Ren_US
dc.identifier.urihttp://hdl.handle.net/10072/399091
dc.description.abstractThe androgen receptor (AR) is a major driver of prostate cancer (PCa) and a key therapeutic target for AR inhibitors (ie, Enzalutamide). However, Enzalutamide only inhibits androgen-dependent AR signaling, enabling intrinsic AR activation via androgen-independent pathways, leading to aggressive castration-resistant PCa (CRPC). We investigated the ability of novel anti-cancer agents, Dp44mT and DpC, to overcome androgen resistance. The effect of Dp44mT and DpC on androgen-dependent and independent AR signaling was assessed in androgen-dependent and -independent PCa cells using 2D- and 3D-tissue culture. The clinically trialed DpC was then examined in vivo and compared to Enzalutamide. These agents uniquely promote AR proteasomal degradation and inhibit AR transcription in PCa cells via the upregulation of c-Jun, potently reducing the AR target, prostate-specific antigen (PSA). These agents also inhibited the activation of key molecules in both androgen-dependent and independent AR signaling (ie, EGFR, MAPK, PI3K), which promote CRPC. The clinically trialed DpC also significantly inhibited PCa tumor growth, AR, and PSA expression in vivo, being more potent than Enzalutamide. DpC is a promising candidate for a unique, structurally distinct generation of AR inhibitors that simultaneously target both androgen-dependent and independent arms of AR signaling. No other therapies exhibit such comprehensive and potent AR suppression, which is critical for overcoming the development of androgen resistance.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.language.isoeng
dc.publisherWileyen_US
dc.relation.ispartofpagefrom11511en_US
dc.relation.ispartofpageto11528en_US
dc.relation.ispartofissue9en_US
dc.relation.ispartofjournalFASEB Journalen_US
dc.relation.ispartofvolume34en_US
dc.subject.fieldofresearchBiochemistry and Cell Biologyen_US
dc.subject.fieldofresearchPhysiologyen_US
dc.subject.fieldofresearchMedical Physiologyen_US
dc.subject.fieldofresearchcode0601en_US
dc.subject.fieldofresearchcode0606en_US
dc.subject.fieldofresearchcode1116en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsBiologyen_US
dc.subject.keywordsMolecular Biologyen_US
dc.titleUnique targeting of androgen-dependent and -independent AR signaling in prostate cancer to overcome androgen resistanceen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationLim, SC; Jansson, PJ; Assinder, SJ; Maleki, S; Richardson, DR; Kovacevic, Z, Unique targeting of androgen-dependent and -independent AR signaling in prostate cancer to overcome androgen resistance, FASEB Journal, 2020, 34 (9), pp. 11511-11528en_US
dcterms.dateAccepted2020-05-15
dc.date.updated2020-11-09T04:13:09Z
gro.hasfulltextNo Full Text
gro.griffith.authorRichardson, Des R.


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