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

Wang, Bin; Lo, U‐Ging; Wu, Kaijie; Kapur, Payal; Li, Xiangyang; Huang, Jun; Chen, Wei; Hernández, Elizabeth; Santoyo, John; Ma, Shihong; Pong, Rey-Chen; He, Dalin; C, Yi; Hsieh, Jer‐Tsong

doi:10.1002/ijc.30893

Cited by 25 publications

(15 citation statements)

References 39 publications

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“…U2AF65, SAP155, and U2AF35 were screened to be potential candidates. Thailanstatins (TSTs), mainly TST-D, is able to inhibit AR-V7 gene splicing by blocking the interaction between U2AF65 and SAP155, and interfering binding to polypyrimidine tract between the branch point and the 3′ splice site [ 17 ].…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression

Tong

2021

Cancer Cell Int

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Castration-resistant prostate cancer (CRPC) remains prostate cancer research and treatment bottleneck. Abnormal androgen receptor (AR) activation still has a pivotal role in CRPC. Multiple mechanisms involve the process, of which overabundant AR-V7 mRNA splicing production is currently focused and increasingly studied. However, factually, there is no definite conclusion about regulation of AR-V7 mRNA splicing. Recently developed knowledge has demonstrated that JMJD6 and U2AF65 as a hopeful approach in mRNA splicing regulation. The authors propose a novel possible mechanism elucidating AR mRNA splicing for CRPC progression using dual-function enzyme JMJD6 and its induced JMJD6/U2AF65/AR-V7 axis. In this hypothesis JMJD6 introduces to AR promoter to demethylate H3R or H4R and promotes AR mRNA transcription via its demethylase activity and interaction with U2AF65. It is expected that JMJD6 could further effectively perform U2AF65 hydroxylation to achieve AR-V7 mRNA splicing via its hydroxylase activity.

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Section: Evaluation Of the Hypothesismentioning

confidence: 99%

The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression

Tong

2021

Cancer Cell Int

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“…This inhibition is of utmost importance because none of the drugs available in the market can directly target the full length and splice variants of the AR. However, compounds other than RA have been shown to decrease the levels of AR-FL and AR-Vs pre-clinically [129][130][131]. Taken together, the study provided a rationale for RA and its combination treatment against CRPC.…”

Section: Prostate Cancermentioning

confidence: 81%

Anticancer Potential of Raddeanin A, a Natural Triterpenoid Isolated from Anemone raddeana Regel

et al. 2020

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Natural compounds extracted from plants have gained immense importance in the fight against cancer cells due to their lesser toxicity and potential therapeutic effects. Raddeanin A (RA), an oleanane type triterpenoid is a major compound isolated from Anemone raddeana Regel. As an anticancer agent, RA induces apoptosis, cell cycle arrest, inhibits invasion, migration and angiogenesis in malignant cell lines as well as in preclinical models. In this systemic review, the pharmacological effects of RA and its underlying molecular mechanisms were carefully analyzed and potential molecular targets have been highlighted. The apoptotic potential of RA can be mediated through the modulation of Bcl-2, Bax, caspase-3, caspase-8, caspase-9, cytochrome c and poly-ADP ribose polymerase (PARP) cleavage. PI3K/Akt signaling pathway serves as the major molecular target affected by RA. Furthermore, RA can block cell proliferation through inhibition of canonical Wnt/β-catenin signaling pathway in colorectal cancer cells. RA can also alter the activation of NF-κB and STAT3 signaling pathways to suppress invasion and metastasis. RA has also exhibited promising anticancer potential against drug resistant cancer cells and can enhance the anticancer effects of several chemotherapeutic agents. Overall, RA may function as a promising compound in combating cancer, although further in-depth study is required under clinical settings to validate its efficacy in cancer patients.

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“…That is to target AR-FL and AR-Vs. In addition to RA, several other compounds have been shown pre-clinically to reduce the levels of AR-FL and AR-Vs. 34,[48][49][50][51][52][53][54][55][56][57][58] These compounds may serve as an effective antidote to overcoming resistance to androgen deprivation therapy for treatment of CRPC. 1,2 ).…”

Section: Discussionmentioning

confidence: 99%

Raddeanin A down‐regulates androgen receptor and its splice variants in prostate cancer

Xia

Bai

et al. 2019

J Cellular Molecular Medi

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Castration‐resistant progression of prostate cancer is a major cause of prostate cancer mortality, and increased expression and activity of the full‐length and the splice variants of androgen receptor (AR) have been indicated to drive castration resistance. Consequently, there is an urgent need to develop agents that can target both the full‐length and the splice variants of AR for more effective treatment of prostate cancer. In the present study, we showed that raddeanin A (RA), an oleanane‐type triterpenoid saponin, suppresses the transcriptional activities of both the full‐length and the splice variants of AR. This is attributable to their decreased expression as a result of RA induction of proteasome‐mediated degradation and inhibition of the transcription of the AR gene. We further showed the potential of using RA to enhance the growth inhibitory efficacy of docetaxel, the first‐line chemotherapy for prostate cancer. This study identifies RA as a new agent to target both the full‐length and the splice variants of AR and provides a rationale for further developing RA for prostate cancer treatment.

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

Cited by 25 publications

References 39 publications

The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression

The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression

Anticancer Potential of Raddeanin A, a Natural Triterpenoid Isolated from Anemone raddeana Regel

Raddeanin A down‐regulates androgen receptor and its splice variants in prostate cancer

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