Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Chaohao Li; Nadia A. Lanman; Yifan Kong; Daheng He; Fengyi Mao; Elia Farah; Yanquan Zhang; Jinghui Liu; Chi Wang; Qiou Wei; Xiaoqi Liu

doi:10.1074/jbc.RA119.011385

Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Chaohao Li, Nadia A. Lanman, Yifan Kong, Daheng He, Fengyi Mao, Elia Farah, Yanquan Zhang, Jinghui Liu, Chi Wang, Qiou Wei, Xiaoqi Liu

Research output: Contribution to journal › Article › peer-review

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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
Pages (from-to)	5470-5483
Number of pages	14
Journal	Journal of Biological Chemistry
Volume	295
Issue number	16
DOIs	https://doi.org/10.1074/jbc.RA119.011385
State	Published - Apr 17 2020

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2020 Li et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1074/jbc.RA119.011385

Cite this

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title = "Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance",

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.",

author = "Chaohao Li and Lanman, {Nadia A.} and Yifan Kong and Daheng He and Fengyi Mao and Elia Farah and Yanquan Zhang and Jinghui Liu and Chi Wang and Qiou Wei and Xiaoqi Liu",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2020 Li et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.",

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doi = "10.1074/jbc.RA119.011385",

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AU - Li, Chaohao

AU - Lanman, Nadia A.

AU - Kong, Yifan

AU - He, Daheng

AU - Mao, Fengyi

AU - Farah, Elia

AU - Zhang, Yanquan

AU - Liu, Jinghui

AU - Wang, Chi

AU - Wei, Qiou

AU - Liu, Xiaoqi

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2020 Li et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2020/4/17

Y1 - 2020/4/17

N2 - 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.

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Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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