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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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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DOI: https://doi.org/10.1038/sj.onc.1202690
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