KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer.

Abstract

The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. SIGNIFICANCE: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.

• Authors: Lin Gao, Wenbo Zhang, Jing Zhang, Junmei Liu, Feifei Sun, Hui Liu, Jing Hu, Xin Wang, Xueli Wang, Peng Su, Shouzhen Chen, Sifeng Qu, Benkang Shi, Xueting Xiong, Weiwen Chen, Xuesen Dong, Bo Han
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 4 Pg. 1026-1039 (02 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33277366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• AR protein, human
• Benzamides
• KIF15 protein, human
• Nitriles
• Protein Isoforms
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide
• Kinesins

Topics

• Animals
• Benzamides (therapeutic use)
• Cell Line, Tumor
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• HEK293 Cells
• Humans
• Kinesins (genetics, physiology)
• Male
• Mice
• Mice, Nude
• Nitriles (therapeutic use)
• PC-3 Cells
• Phenylthiohydantoin (therapeutic use)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Domains (genetics)
• Protein Isoforms (genetics, metabolism)
• Protein Stability
• Proteolysis
• Receptors, Androgen (chemistry, genetics, metabolism)