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

J. Chien, E. Wong, E. Nikes, M. J. Noble, C. G. Pantazis, G. V. Shah

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

An abnormal stimulation of cAMP signaling cascade has been implicated in various human carcinomas. Since the agents activating G(s)α-mediated signaling pathways have been shown to increase in vitro proliferation of prostate cancer cells, present studies examined the G(s)α-mediated signaling in tumorigenicity and invasiveness of PC-3M prostate cancer cells. PC-3M cells were stably transfected with plasmids containing either wild type (G(s)α-WT) or constitutively active (gsp mutant of G(s)α or G(s)α-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 G(s)α-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 G(s)α-WT. G(s)α-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 G(s)α-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 G(s)α-WT reduced the ability of PC-3M cells to form tumors in nude mice. These results suggest that persistent activation of G(s)α-mediated signaling cascade can dramatically accelerate tumorigenesis and metastasizing ability of prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)3376-3382
Number of pages7
JournalOncogene
Volume18
Issue number22
DOIs
StatePublished - Jun 3 1999
Externally publishedYes

Keywords

  • G(s)α
  • Invasiveness
  • Prostate cancer
  • Tumorigenicity

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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