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

Abstract

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

• Authors: J Chien, E Wong, E Nikes, M J Noble, C G Pantazis, G V Shah
• Journal: Oncogene (Oncogene) Vol. 18 Issue 22 Pg. 3376-82 (Jun 03 1999) ISSN: 0950-9232 [Print] England
• PMID: 10362358 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• GTP-Binding Protein alpha Subunits, Gs

Topics

• Animals
• Carcinogenicity Tests
• Carcinoma (metabolism, pathology, secondary)
• Cell Movement
• GTP-Binding Protein alpha Subunits, Gs (genetics, metabolism)
• Humans
• Kidney Neoplasms (metabolism, pathology, secondary)
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Neoplasm Invasiveness
• Prostatic Neoplasms (metabolism, pathology)
• Signal Transduction
• Tumor Cells, Cultured
• Tumor Stem Cell Assay