Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer

Bin Wang, U. Ging Lo, Kaijie Wu, Payal Kapur, Xiangyang Liu, Jun Huang, Wei Chen, Elizabeth Hernandez, John Santoyo, Shi Hong Ma, Rey Chen Pong, Dalin He, Yiqiang Cheng, Jer Tsong Hsieh

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3′ splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application.

Original languageEnglish
Pages (from-to)2121-2130
Number of pages10
JournalInternational Journal of Cancer
Volume141
Issue number10
DOIs
StatePublished - 15 Nov 2017

Fingerprint

Castration
Androgen Receptors
Prostatic Neoplasms
RNA Splice Sites
Survival
Heterografts
Genes
Apoptosis
Ligands
Messenger RNA
Growth
Pharmaceutical Preparations
Neoplasms
Proteins

Keywords

  • AR variants
  • CRPC
  • gene splicing
  • thailanstatin

Cite this

Wang, Bin ; Lo, U. Ging ; Wu, Kaijie ; Kapur, Payal ; Liu, Xiangyang ; Huang, Jun ; Chen, Wei ; Hernandez, Elizabeth ; Santoyo, John ; Ma, Shi Hong ; Pong, Rey Chen ; He, Dalin ; Cheng, Yiqiang ; Hsieh, Jer Tsong. / Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer. In: International Journal of Cancer. 2017 ; Vol. 141, No. 10. pp. 2121-2130.
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abstract = "The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3′ splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application.",
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Wang, B, Lo, UG, Wu, K, Kapur, P, Liu, X, Huang, J, Chen, W, Hernandez, E, Santoyo, J, Ma, SH, Pong, RC, He, D, Cheng, Y & Hsieh, JT 2017, 'Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer', International Journal of Cancer, vol. 141, no. 10, pp. 2121-2130. https://doi.org/10.1002/ijc.30893

Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer. / Wang, Bin; Lo, U. Ging; Wu, Kaijie; Kapur, Payal; Liu, Xiangyang; Huang, Jun; Chen, Wei; Hernandez, Elizabeth; Santoyo, John; Ma, Shi Hong; Pong, Rey Chen; He, Dalin; Cheng, Yiqiang; Hsieh, Jer Tsong.

In: International Journal of Cancer, Vol. 141, No. 10, 15.11.2017, p. 2121-2130.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer

AU - Wang, Bin

AU - Lo, U. Ging

AU - Wu, Kaijie

AU - Kapur, Payal

AU - Liu, Xiangyang

AU - Huang, Jun

AU - Chen, Wei

AU - Hernandez, Elizabeth

AU - Santoyo, John

AU - Ma, Shi Hong

AU - Pong, Rey Chen

AU - He, Dalin

AU - Cheng, Yiqiang

AU - Hsieh, Jer Tsong

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