SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition.
SSeCKS, a Src-suppressed protein kinase C substrate with metastasis suppressor activity, is the rodent orthologue of human gravin/AKAP12, a scaffolding protein for protein kinase A and protein kinase C. We show here that the tetracycline-regulated reexpression of SSeCKS in MatLyLu (MLL) prostate cancer cells suppressed formation of macroscopic lung metastases in both spontaneous and experimental models of in vivo metastasis while having minimal inhibitory effects on the growth of primary-site s.c. tumors. SSeCKS decreased angiogenesis in vitro and in vivo by suppressing vascular endothelial growth factor (VEGF) expression in MLL tumor cells as well as in stromal cells. The forced reexpression of VEGF(165) and VEGF(121) isoforms was sufficient to reverse aspects of SSeCKS metastasis-suppressor activity in both the experimental and spontaneous models. SSeCKS reexpression in MLL cells resulted in the down-regulation of proangiogenic genes, such as osteopontin, tenascin C, KGF, angiopoietin, HIF-1alpha, and PDGFRbeta, and the up-regulation of antiangiogenic genes, such as vasostatin and collagen 18a1, a precursor of endostatin. These results suggest that SSeCKS suppresses formation of metastatic lesions by inhibiting VEGF expression and by inducing soluble antiangiogenic factors.
Su
Bing
B
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA.
Zheng
Qiao
Q
Vaughan
Mary M
MM
Bu
Yahao
Y
Gelman
Irwin H
IH
D054758:A Kinase Anchor Proteins; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017154:Stromal Cells / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; C491161:Akap12 protein, mouse; C102361:Akap12 protein, rat; D018797:Cell Cycle Proteins; D011506:Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A