Androgen receptor splicing variant 7 (ARV7) inhibits docetaxel sensitivity by inactivating the spindle assembly checkpoint.

Abstract

The clinical efficacy of docetaxel (DTX) in prostate cancer treatment is barely satisfactory due to diverse responses of the patients, including the development of resistance. Recently, aberrant androgen receptor (AR) signaling, including expression of the constitutively active ARV7, was reported to contribute to DTX resistance. However, the underlying molecular mechanism remains largely unknown. Of note, previous studies have highlighted that ARV7, unlike its parental AR, potentially favors the expression of some genes involved in cell cycle progression. Since DTX mainly targets microtubule dynamics and mitosis, we wanted to test whether ARV7 plays a specific role in mitotic regulation and whether this activity is involved in DTX resistance. In the present study, we found that ARV7 mediates DTX sensitivity through inactivating the spindle assembly checkpoint (SAC) and promoting mitotic slippage. By shifting the balance to the slippage pathway, ARV7-expressing cells are more likely to escape from mitotic death induced by acute DTX treatment. Furthermore, we also identified E2 enzyme UBE2C as the primary downstream effector of ARV7 in promoting the SAC inactivation and premature degradation of cyclin B1. Moreover, we showed that combination treatment of DTX and an inhibitor of mitotic exit can exert synergistic effect in high ARV7-expressing prostate cancer cells. In sum, our work identified a novel role of ARV7 in promoting DTX resistance and offering a potential path to combat DTX resistance related to abnormal activation of the AR signaling and mitotic dysregulation.

• Authors: Bingbing Yu, Yanan Liu, Haoge Luo, Jiaying Fu, Yang Li, Chen Shao
• Journal: The Journal of biological chemistry (J Biol Chem) 2021 Jan-Jun Vol. 296 Pg. 100276 ISSN: 1083-351X [Electronic] United States
• PMID: 33428943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Neoplasm Proteins
• Receptors, Androgen
• Docetaxel

Topics

• Cell Cycle Checkpoints (drug effects, genetics)
• Docetaxel (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Humans
• Male
• Mitosis (drug effects, genetics)
• Neoplasm Proteins (genetics, metabolism)
• PC-3 Cells
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Spindle Apparatus (genetics, metabolism)