Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis

Srinivas Nandana, Manish Tripathi, Peng Duan, Chia Yi Chu, Rajeev Mishra, Chunyan Liu, Renjie Jin, Hironobu Yamashita, Majd Zayzafoon, Neil A. Bhowmick, Haiyen E. Zhau, Robert J. Matusik, Leland W.K. Chung

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Identification of factors that mediate visceral and bone metastatic spread and subsequent bone remodeling events is highly relevant to successful therapeutic intervention in advanced human prostate cancer. TBX2, a T-box family transcription factor that negatively regulates cell-cycle inhibitor p21, plays critical roles during embryonic development, and recent studies have highlighted its role in cancer. Here, we report that TBX2 is overexpressed in human prostate cancer specimens and bone metastases from xenograft mouse models of human prostate cancer. Blocking endogenous TBX2 expression in PC3 and ARCaPM prostate cancer cell models using a dominant-negative construct resulted in decreased tumor cell proliferation, colony formation, and invasion in vitro. Blocking endogenous TBX2 in human prostate cancer mouse xenografts decreased invasion and abrogation of bone and soft tissue metastasis. Furthermore, blocking endogenous TBX2 in prostate cancer cells dramatically reduced bone-colonizing capability through reduced tumor cell growth and bone remodeling in an intratibial mouse model. TBX2 acted in trans by promoting transcription of the canonical WNT (WNT3A) promoter. Genetically rescuing WNT3A levels in prostate cancer cells with endogenously blocked TBX2 partially restored the TBX2-induced prostate cancer metastatic capability in mice. Conversely, WNT3A-neutralizing antibodies or WNT antagonist SFRP-2 blocked TBX2-induced invasion. Our findings highlight TBX2 as a novel therapeutic target upstream of WNT3A, whereWNT3Aantagonists could be novel agents for the treatment of metastasis and for skeletal complications in prostate cancer patients.

Original languageEnglish (US)
Pages (from-to)1331-1344
Number of pages14
JournalCancer Research
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2017
Externally publishedYes

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Prostatic Neoplasms
Neoplasm Metastasis
Bone and Bones
Bone Remodeling
Heterografts
Bone Neoplasms
Neoplasms
Neutralizing Antibodies
Embryonic Development
Cell Cycle
Transcription Factors
Therapeutics
Cell Proliferation
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis. / Nandana, Srinivas; Tripathi, Manish; Duan, Peng; Chu, Chia Yi; Mishra, Rajeev; Liu, Chunyan; Jin, Renjie; Yamashita, Hironobu; Zayzafoon, Majd; Bhowmick, Neil A.; Zhau, Haiyen E.; Matusik, Robert J.; Chung, Leland W.K.

In: Cancer Research, Vol. 77, No. 6, 15.03.2017, p. 1331-1344.

Research output: Contribution to journalArticle

Nandana, S, Tripathi, M, Duan, P, Chu, CY, Mishra, R, Liu, C, Jin, R, Yamashita, H, Zayzafoon, M, Bhowmick, NA, Zhau, HE, Matusik, RJ & Chung, LWK 2017, 'Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis', Cancer Research, vol. 77, no. 6, pp. 1331-1344. https://doi.org/10.1158/0008-5472.CAN-16-0497
Nandana, Srinivas ; Tripathi, Manish ; Duan, Peng ; Chu, Chia Yi ; Mishra, Rajeev ; Liu, Chunyan ; Jin, Renjie ; Yamashita, Hironobu ; Zayzafoon, Majd ; Bhowmick, Neil A. ; Zhau, Haiyen E. ; Matusik, Robert J. ; Chung, Leland W.K. / Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis. In: Cancer Research. 2017 ; Vol. 77, No. 6. pp. 1331-1344.
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