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Constitutive activation of stimulatory guanine nucleotide binding protein (GSαQL)-mediated signaling increases invasiveness and tumorigenicity of PC-3M prostate cancer cells

Oncogene volume 18, pages 3376–3382 (1999)Cite this article

Abstract

An abnormal stimulation of cAMP signaling cascade has been implicated in various human carcinomas. Since the agents activating GSα-mediated signaling pathways have been shown to increase in vitro proliferation of prostate cancer cells, present studies examined the GSα-mediated signaling in tumorigenicity and invasiveness of PC-3M prostate cancer cells. PC-3M cells were stably transfected with plasmids containing either wild type (GSα-WT) or constitutively active (gsp mutant of GSα or GSα-QL) cDNAs. The stable transfectants were then tested for: (1) colony formation in soft agar; (2) cell migration and penetration of basement matrix in an in vitro invasion assay; and (3) the ability to form tumors and metastases in nude mice. PC-3M cells expressing GSα-QL protein displayed 15-fold increase in their ability to migrate and penetrate the basement membrane as compared to parental PC-3M cells or those expressing GSα-WT. GSα-QL transfectants also displayed a dramatically greater rate of growth in soft agar, and greater tumorigenicity and metastasis forming ability when orthotopically implanted in nude mice. All mice receiving PC-3M cells produced primary tumors within 5 weeks after implantation. However, the cells expressing GSα-QL displayed a significantly faster tumor growth as assessed by prostate weight (greater than 20-fold as compared to PC-3M cells), and produced metastases in kidneys, lymph nodes, blood vessels, bowel mesentery and intestine. Interestingly, expression of GSα-WT reduced the ability of PC-3M cells to form tumors in nude mice. These results suggest that persistent activation of GSα-mediated signaling cascade can dramatically accelerate tumorigenesis and metastasizing ability of prostate cancer cells.

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Acknowledgements

This work was supported by grant DK-45044 (to GV Shah) from the National Institutes of Health. Authors thank Dr R Iyengar for providing plasmids GSα-WT and GSα-QL.

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Authors and Affiliations

  1. Department of Urologic Surgery, University of Kansas Medical Center, Kansas City, 66160, Kansas, USA

    E Nikes, M J Noble & G V Shah

  2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, 66160, Kansas, USA

    J Chien & G V Shah

  3. Department of Pathology, University of Kansas Medical Center, Kansas City, 66160, Kansas, USA

    E Wong & C G Pantazis

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  1. J Chien
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Chien, J., Wong, E., Nikes, E. et al. Constitutive activation of stimulatory guanine nucleotide binding protein (GSαQL)-mediated signaling increases invasiveness and tumorigenicity of PC-3M prostate cancer cells. Oncogene 18, 3376–3382 (1999). https://doi.org/10.1038/sj.onc.1202690

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