PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-Resistant prostate cancer

Yinhui Yang, Yang Bai, Yundong He, Yu Zhao, Jiaxiang Chen, Linlin Ma, Yunqian Pan, Michael Hinten, Jun Zhang, Robert Jeffrey Karnes, Manish Kohli, Jennifer J Westendorf, Benyi Li, Runzhi Zhu, Haojie Huang, Wanhai Xu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)–GPRC6A–CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines. Pten knockout mice were used to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results: We uncovered that activation of the AKT–RUNX2–OCN–GPRC6A–CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions: Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null prostate cancer, including CRPC.

Original languageEnglish (US)
Pages (from-to)834-846
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number4
DOIs
StatePublished - Feb 15 2018

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Tumor Microenvironment
Castration
Androgens
Testosterone
Prostatic Neoplasms
Cholesterol Side-Chain Cleavage Enzyme
Cell Line
Osteocalcin
Prodrugs
Androgen Receptors
Collagenases
Knockout Mice
Prostate
Neoplasms
Carcinogenesis
Research Design
Gene Expression
Growth
Abiraterone Acetate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-Resistant prostate cancer. / Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, Robert Jeffrey; Kohli, Manish; Westendorf, Jennifer J; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai.

In: Clinical Cancer Research, Vol. 24, No. 4, 15.02.2018, p. 834-846.

Research output: Contribution to journalArticle

Yang, Yinhui ; Bai, Yang ; He, Yundong ; Zhao, Yu ; Chen, Jiaxiang ; Ma, Linlin ; Pan, Yunqian ; Hinten, Michael ; Zhang, Jun ; Karnes, Robert Jeffrey ; Kohli, Manish ; Westendorf, Jennifer J ; Li, Benyi ; Zhu, Runzhi ; Huang, Haojie ; Xu, Wanhai. / PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-Resistant prostate cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 4. pp. 834-846.
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abstract = "Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)–GPRC6A–CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines. Pten knockout mice were used to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results: We uncovered that activation of the AKT–RUNX2–OCN–GPRC6A–CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions: Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null prostate cancer, including CRPC.",
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T1 - PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-Resistant prostate cancer

AU - Yang, Yinhui

AU - Bai, Yang

AU - He, Yundong

AU - Zhao, Yu

AU - Chen, Jiaxiang

AU - Ma, Linlin

AU - Pan, Yunqian

AU - Hinten, Michael

AU - Zhang, Jun

AU - Karnes, Robert Jeffrey

AU - Kohli, Manish

AU - Westendorf, Jennifer J

AU - Li, Benyi

AU - Zhu, Runzhi

AU - Huang, Haojie

AU - Xu, Wanhai

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)–GPRC6A–CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines. Pten knockout mice were used to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results: We uncovered that activation of the AKT–RUNX2–OCN–GPRC6A–CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions: Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null prostate cancer, including CRPC.

AB - Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)–GPRC6A–CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines. Pten knockout mice were used to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results: We uncovered that activation of the AKT–RUNX2–OCN–GPRC6A–CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions: Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null prostate cancer, including CRPC.

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U2 - 10.1158/1078-0432.CCR-17-2006

DO - 10.1158/1078-0432.CCR-17-2006

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VL - 24

SP - 834

EP - 846

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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