Abstract
Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.
Original language | English |
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Pages (from-to) | 5470-5483 |
Number of pages | 14 |
Journal | Journal of Biological Chemistry |
Volume | 295 |
Issue number | 16 |
DOIs | |
State | Published - Apr 17 2020 |
Bibliographical note
Publisher Copyright:© 2020 Li et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
Funding
This work was supported by National Institutes of Health Grants R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X. L.) and Biostatistics and Bioinformatics Shared Resources of the University of Kentucky Markey Cancer Center Grant P30CA177558. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. thank Dr. Qiou Wei for providing three months of accommodation to us at the University of Kentucky. This work was supported by National Institutes of Health Grants R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X. L.) and Biostatistics and Bioinformatics Shared Resources of the University of Ken-tucky Markey Cancer Center Grant P30CA177558. The authors declare that they have no conflicts of interest with the contents of this article. The con-tent is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funders | Funder number |
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University of Ken-tucky Markey Cancer Center | |
National Institutes of Health (NIH) | R01 CA192894, R01 CA196835, R01 CA196634, R01 CA157429 |
National Childhood Cancer Registry – National Cancer Institute | P30CA177558 |
University of Kentucky Markey Cancer Center |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology