Androgen receptor splice variant 7 functions independently of the full length receptor in prostate cancer cells

Liang, Jintai; Wang, Liyang; Poluben, Larysa; Nouri, Mannan; Arai, Seiji; Xie, Lisha; Voznesensky, Olga; Cato, Laura; Yuan, Xin; Russo, Joshua W.; Long, Henry W.; Brown, Myles; Chen, Shaoyong; Balk, Steven P.

doi:10.1016/j.canlet.2021.07.013

Cited by 16 publications

(14 citation statements)

References 48 publications

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“…The current study defined BlCa AR-driven transcriptional output to identify exploitable downstream vulnerabilities. We found that T-AR and AR isoforms regulate distinct cohorts of genes, but with an overlapping transcript population, similarly to what has been reported for prostatic malignancies [32][33][34][35][36] . An abrupt cessation of all AR signaling results in the downregulation of transcripts associated with proliferative biosynthetic processes and coordinately, an elevation of transcripts encoding proteins that negatively regulate these processes, pro-apoptotic proteins, and markers of hypoxia arguing that AR is instrumental in promoting metabolic activities.…”

Section: Discussionsupporting

confidence: 86%

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells

Katleba

Tsamouri

Jathal

et al. 2023

Sci Rep

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The observed sex disparity in bladder cancer (BlCa) argues that androgen receptor (AR) signaling has a role in these malignancies. BlCas express full-length AR (FL-AR), constitutively active AR splice variants, including AR-v19, or both, and their depletion limits BlCa viability. However, the mechanistic basis of AR-dependence is unknown. Here, we depleted FL-AR, AR-v19, or all AR forms (T-AR), and performed RNA-seq studies to uncover that different AR forms govern distinct but partially overlapping transcriptional programs. Overlapping alterations include a decrease in mTOR and an increase of hypoxia regulated transcripts accompanied by a decline in oxygen consumption rate (OCR). Queries of BlCa databases revealed a significant negative correlation between AR expression and multiple hypoxia-associated transcripts arguing that this regulatory mechanism is a feature of high-grade malignancies. Our analysis of a 1600-compound library identified niclosamide as a strong ATPase inhibitor that reduces OCR in BlCa cells, decreased cell viability and induced apoptosis in a dose and time dependent manner. These results suggest that BlCa cells hijack AR signaling to enhance metabolic activity, promoting cell proliferation and survival; hence targeting this AR downstream vulnerability presents an attractive strategy to limit BlCa.

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Section: Discussionsupporting

confidence: 86%

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells

Katleba

Tsamouri

Jathal

et al. 2023

Sci Rep

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“…Similarly, some investigators have identified unique AR-V7 chromatin binding sites, while others have described these as artifacts/unreliable 16,17,19,40 . Some investigators have concluded that AR-V7 acts with and/or requires AR for activity whereas others describe AR-V7 actions as independent of AR 14,16,24,29 . Many of the studies have been done in LN95 and 22RV1 cells 14 , which endogenously express low level of variants, and/or also express other active variants 41 , but neither cell line was derived from a tumor expressing variants 20,21 .…”

Section: Discussionmentioning

confidence: 99%

“…Some investigators have concluded that AR-V7 acts with and/or requires AR for activity whereas others describe AR-V7 actions as independent of AR 14,16,24,29 . Many of the studies have been done in LN95 and 22RV1 cells 14 , which endogenously express low level of variants, and/or also express other active variants 41 , but neither cell line was derived from a tumor expressing variants 20,21 . These lines also have undergone changes during their derivation 42 , so there is no AR only line suitable for a direct comparison.…”

Section: Discussionmentioning

confidence: 99%

“…A major limitation in evaluating the role of AR-V7 is the lack of appropriate cell models. Many studies have relied on two cell lines, LNCaP95 (LN95) and 22RV1 14,[16][17][18][19] , which endogenously express AR-V7, but are both derivatives of tumors that did not originally express AR-V7. LN95 is a derivative of LNCaP cells 20 and 22RV1 cells were derived from an androgen dependent patient derived xenograft (PDX) that developed resistance subsequent to castration of the mouse 21 .…”

Section: Introductionmentioning

confidence: 99%

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Cistrome and transcriptome analysis identifies unique androgen receptor (AR) and AR- V7 splice variant chromatin binding and transcriptional activities

Basil

Robertson

Bingman

et al. 2021

Preprint

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The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and AR-V7. The two AR isoforms shared many targets, but overall had distinct transcriptomes. Optimal induction of novel targets sometimes required more receptor isoform than classical targets such as PSA. The isoforms displayed remarkably different cistromes with numerous differential binding sites. Some of the unique AR-V7 sites were located proximal to the transcription start sites (TSS). A de novo binding motif similar to a half ARE was identified in many AR-V7 preferential sites and, in contrast to conventional half ARE sites that bind AR-V7, FOXA1 was not enriched at these sites. This supports the concept that the AR isoforms have unique actions with the potential to serve as biomarkers or novel therapeutic targets.

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“…However, AR-V7 lacks the LBD, and we are investigating a possible alternative mechanism of degradation that may overlap with the model presented for fAR. A recent study demonstrates that AR-V7 functions differently and is independent of fAR [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Novel AR/AR-V7 and Mnk1/2 Degrader, VNPP433-3β: Molecular Mechanisms of Action and Efficacy in AR-Overexpressing Castration Resistant Prostate Cancer In Vitro and In Vivo Models

Thomas

Thankan

Purushottamachar

et al. 2022

Cells

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Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR with E3 ligases MDM2/CHIP but disrupting AR-HSP90 binding. Next, VNPP433-3β decreases phosphorylation of 4EBP1 and abates binding of eIF4E and eIF4G to 5′ cap of mRNA by depleting MNK1/2 with consequent depletion of phosphorylated eIF4E. Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5′cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo.

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Androgen receptor splice variant 7 functions independently of the full length receptor in prostate cancer cells

Cited by 16 publications

References 48 publications

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells

Cistrome and transcriptome analysis identifies unique androgen receptor (AR) and AR- V7 splice variant chromatin binding and transcriptional activities

Novel AR/AR-V7 and Mnk1/2 Degrader, VNPP433-3β: Molecular Mechanisms of Action and Efficacy in AR-Overexpressing Castration Resistant Prostate Cancer In Vitro and In Vivo Models

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