The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer.
The molecular mechanisms leading to prostate cancer remain poorly understood, especially concerning the progression to the metastatic form. SSeCKS, a major protein kinase C substrate with tumor suppressor activity, is likely the rodent orthologue of human Gravin/AKAP12, a scaffolding protein for protein kinases A and C. Gravin was mapped as a single-copy gene to 6q24-25.2, a hotspot for deletion in advanced prostate cancer, and therefore, we investigated the role of SSeCKS/Gravin in prostate oncogenesis. SSeCKS/Gravin protein was detected in untransformed rat and human prostate epithelial cell lines EP12 and PZ-HPV-7, respectively, and in human prostatic epithelium, especially basal epithelial cells. In contrast, SSeCKS/Gravin protein and RNA levels were severely reduced in human (PC-3, PPC-1, LNCaP, DU145, and TSU) and rat Dunning (AT3.1 and MatLyLu) prostate cancer cell lines. The regulated reexpression of SSeCKS in MatLyLu cells induced filopodia-like projections and a decrease in anchorage-independent growth. In nude mice, SSeCKS reexpression slightly decreased primary-site tumor growth but severely decreased the formation of lung metastases. Primary-site tumors that progressed lost regulated SSeCKS reexpression. SSeCKS/Gravin expression was detected in benign human prostatic lesions and well-differentiated carcinomas but not in undifferentiated lesions with Gleason sums > or =6. Our data suggest a role for the loss of SSeCKS/Gravin in the metastatic progression of human prostate cancer.
Xia
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Departments of Microbiology, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Unger
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Miller
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Nelson
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Gelman
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D054758:A Kinase Anchor Proteins; D000818:Animals; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002871:Chromosome Banding; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens / Q000235:genetics* / Q000502:physiology; D008970:Molecular Weight; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013752:Tetracycline / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; C491161:Akap12 protein, mouse; C102361:Akap12 protein, rat; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D008934:Mitogens; D020033:Protein Isoforms; D011506:Proteins; D012334:RNA, Neoplasm; D013752:Tetracycline