RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype

Dazhi Yang, Noemi Kedei, Luowei Li, Juan Tao, Julia F. Velasquez, Aleksandra M. Michalowski, Balázs I. Tóth, Rita Marincsák, Attila Varga, T. Bíró, Stuart H. Yuspa, Peter M. Blumberg

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

RasGRP3 mediates the activation of the Ras signaling pathway that is present in many human cancers. Here, we explored the involvement of RasGRP3 in the formation and maintenance of the prostate cancer phenotype. RasGRP3 expression was elevated in multiple human prostate tumor tissue samples and in the human androgen-independent prostate cancer cell lines PC-3 and DU 145 compared with the androgen-dependent prostate cancer cell line LNCaP. Downregulation of endogenous RasGRP3 in PC-3 and DU 145 cells reduced Ras-GTP formation, inhibited cell proliferation, impeded cell migration, and induced apoptosis. Anchorage-independent growth of the PC-3 cells and tumor formation in mouse xenografts of both cell lines were likewise inhibited. Inhibition of RasGRP3 expression reduced AKT and extracellular signal-regulated kinase 1/2 phosphorylation and sensitized the cells to killing by carboplatin. Conversely, exogenous RasGRP3 elevated Ras-GTP, stimulated proliferation, and provided resistance to phorbol 12-myristate 13-acetate-induced apoptosis in LNCaP cells. RasGRP3-overexpressing LNCaP cells displayed a markedly enhanced rate of xenograft tumor formation in both male and female mice compared with the parental line. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses, caused the cells to resume the LNCaP morphology, and suppressed growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. We conclude that RasGRP3 contributes to the malignant phenotype of the prostate cancer cells and may constitute a novel therapeutic target for human prostate cancer.

Original languageEnglish
Pages (from-to)7905-7917
Number of pages13
JournalCancer Research
Volume70
Issue number20
DOIs
Publication statusPublished - Oct 15 2010

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Prostatic Neoplasms
Maintenance
Phenotype
Guanosine Triphosphate
Heterografts
Cell Line
Androgens
Neoplasms
Apoptosis
Mitogen-Activated Protein Kinase 3
Carboplatin
Mitogen-Activated Protein Kinase 1
Growth
Cell Movement
Prostate
Acetates
Down-Regulation
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yang, D., Kedei, N., Li, L., Tao, J., Velasquez, J. F., Michalowski, A. M., ... Blumberg, P. M. (2010). RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. Cancer Research, 70(20), 7905-7917. https://doi.org/10.1158/0008-5472.CAN-09-4729

RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. / Yang, Dazhi; Kedei, Noemi; Li, Luowei; Tao, Juan; Velasquez, Julia F.; Michalowski, Aleksandra M.; Tóth, Balázs I.; Marincsák, Rita; Varga, Attila; Bíró, T.; Yuspa, Stuart H.; Blumberg, Peter M.

In: Cancer Research, Vol. 70, No. 20, 15.10.2010, p. 7905-7917.

Research output: Contribution to journalArticle

Yang, D, Kedei, N, Li, L, Tao, J, Velasquez, JF, Michalowski, AM, Tóth, BI, Marincsák, R, Varga, A, Bíró, T, Yuspa, SH & Blumberg, PM 2010, 'RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype', Cancer Research, vol. 70, no. 20, pp. 7905-7917. https://doi.org/10.1158/0008-5472.CAN-09-4729
Yang D, Kedei N, Li L, Tao J, Velasquez JF, Michalowski AM et al. RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. Cancer Research. 2010 Oct 15;70(20):7905-7917. https://doi.org/10.1158/0008-5472.CAN-09-4729
Yang, Dazhi ; Kedei, Noemi ; Li, Luowei ; Tao, Juan ; Velasquez, Julia F. ; Michalowski, Aleksandra M. ; Tóth, Balázs I. ; Marincsák, Rita ; Varga, Attila ; Bíró, T. ; Yuspa, Stuart H. ; Blumberg, Peter M. / RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. In: Cancer Research. 2010 ; Vol. 70, No. 20. pp. 7905-7917.
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