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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.issn0892-6638
dc.identifier.doi10.1096/fj.201903167R
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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofpagefrom11511
dc.relation.ispartofpageto11528
dc.relation.ispartofissue9
dc.relation.ispartofjournalFASEB Journal
dc.relation.ispartofvolume34
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchZoology
dc.subject.fieldofresearchMedical physiology
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3109
dc.subject.fieldofresearchcode3208
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiology
dc.subject.keywordsMolecular Biology
dc.titleUnique targeting of androgen-dependent and -independent AR signaling in prostate cancer to overcome androgen resistance
dc.typeJournal article
dc.type.descriptionC1 - Articles
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. 11511-11528
dcterms.dateAccepted2020-05-15
dc.date.updated2020-11-09T04:13:09Z
gro.hasfulltextNo Full Text
gro.griffith.authorRichardson, Des R.


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