KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer
- 15 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (4), 1026-1039
- https://doi.org/10.1158/0008-5472.CAN-20-1965
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 filly 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.Other Versions
Funding Information
- National Natural Science Foundation of China (81672554, 81472417, 81972416)
- Natural Science of ShanDong Province (ZR2019LZL014)
- Major Science and Technology Innovation Project of Shandong Province (2018CXGC1210)
- National Key Research and Development Program of China (2018YFC0114703)
- Fundamental Research Funds of Shandong University (2018JC016)
- Shandong Provincial Major Scientific and Technological Innovation (2017CXGC1201)
- Canadian Institute of Health Research (MOP-137007)
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