Androgen receptor splicing variant 7 (ARV7) inhibits docetaxel sensitivity by inactivating the spindle assembly checkpoint
| Autor: | Haoge Luo, Chen Shao, Jiaying Fu, Bingbing Yu, Yang Li, Yanan Liu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Mad2 Docetaxel Biochemistry mitotic slippage LBD ligand-binding domain FACS fluorescence-activated cell sorting MCC mitotic checkpoint complex Cyclin B1 PSA prostate-specific antigen Chemistry BubR1 mitotic checkpoint serine/threonine-protein kinase BUB1 beta CRPC castration-resistant prostate cancer prostate cancer Neoplasm Proteins Spindle checkpoint Receptors Androgen PC-3 Cells ARV7 androgen receptor splicing variant 7 Research Article Mad2 mitotic arrest deficient 2 Mitosis ADT androgen-deprivation therapy PCa prostate cancer CDC20 Spindle Apparatus DTX docetaxel APC/C anaphase-promoting complex/cyclosome spindle assembly checkpoint AR-FL androgen receptor (full-length) 03 medical and health sciences Humans Molecular Biology 030102 biochemistry & molecular biology Mitotic checkpoint complex Prostatic Neoplasms Cell Biology Cell Cycle Checkpoints ARV7 UBE2C ubiquitin-conjugating enzymes 2C Androgen receptor 030104 developmental biology SASP senescence-associated secretary phenotype Mitotic exit Drug Resistance Neoplasm CDC20 cell division cycle protein 20 Cancer research AR androgen receptor UBE2C OE overexpression SAC spindle assembly checkpoint |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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