Cell adhesion molecules (CAMs) play critical roles in the development and differentiation of multicellular organisms. Recent studies indicate that defects in CAM genes or in their expression may be related to cancer progression. C-CAM is an epithelial CAM of the Ig supergene family. Our studies show that in prostate C-CAM is mainly expressed in the epithelial cells and its expression is regulated by androgen. Down-regulation or complete loss of C-CAM expression was observed in prostate intraepithelial neoplasia (PIN) and prostate cancer, suggesting that C-CAM may be essential in maintinaing a normal prostate. Consistent with this observation, we demonstrated that transfection of C-CAM1 into the prostate cancer cell lines. PC-3 or DU145 markedly reduced their tumorigenicity. In contrast, transfection of a C-CAM1 antisense gene into a non-tumorigenic NbE cells rendered them tumorigenic. These results suggest that C-CAM1 has growth suppressive function. Based on these results, we propose to investigate the mechanims by which C-CAM1affects the growth and tumorigenicity of prostate cancer cells. C-CAM1 may suppress the tumorigenicity of prostate cancer cells because expression of C-CAM1 activates a signaling pathway that changes the """"""""diferentiation state"""""""" of these cells and thus interferes with tumor cell growth. We previously proposed to delineate the tumor suppressor domain in C-CAM by deletion analysis. We have accomplished this goal and showed that the C- terminal cytoplasmic domain but ot the extracellular adhesion domain of C-CAM1 is critical in mediating its tumor-suppressive activity. We also proposed to identify and clone cellular proteins that interact with C-CAM1. Several candidate interacting molecules have been identified. We plan to continue this study by accomplishing the following Specific Aims: 1. To determine whether the cytoplasmic domain of C-CAM1 is sufficient for eliciting tumor suppression. We have shown that the cytoplasmic domain of C-CAM is required for the tumor suppression. Whether this cytoplasmic domain by itself is sufficient for this activity is not clear. We will examine the effects of this cytoplasmic domain (in the absence of other domains from C- CAM1) on interacting proteins. Several candidate C-CAM1- interacting proteins have been identified by chemical cross-linking, yeast two-hybrid, and expression library screening approaches. We will further characterize these proteins and perform functional assays to assess their roles in C-CAM1-mediated growth suppression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG2-PTHB (01))
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
Zip Code
Vakar-Lopez, Funda; Cheng, Chien-Jui; Kim, Jeri et al. (2004) Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol 203:688-95
Abou-Rjaily, George A; Lee, Sang Jun; May, Denisa et al. (2004) CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation. J Clin Invest 114:944-52
Phan, Dillon; Cheng, Chien-Jui; Galfione, Matthew et al. (2004) Identification of Sp2 as a transcriptional repressor of carcinoembryonic antigen-related cell adhesion molecule 1 in tumorigenesis. Cancer Res 64:3072-8
Pu, Yeong-Shiau; Do, Kim-Anh; Luo, Weiping et al. (2002) Enhanced suppression of prostate tumor growth by combining C-CAM1 gene therapy and angiogenesis inhibitor TNP-470. Anticancer Drugs 13:743-9
Sweeney, Paul; El-Naggar, Adel K; Lin, Sue-Hwa et al. (2002) Biological significance of c-met over expression in papillary renal cell carcinoma. J Urol 168:51-5
Volpert, Olga; Luo, Weiping; Liu, Ta-Jen et al. (2002) Inhibition of prostate tumor angiogenesis by the tumor suppressor CEACAM1. J Biol Chem 277:35696-702
Phan, D; Sui, X; Chen, D T et al. (2001) Androgen regulation of the cell-cell adhesion molecule-1 (Ceacam1) gene. Mol Cell Endocrinol 184:115-23
Aumais, J P; Tunstead, J R; McNeil, R S et al. (2001) NudC associates with Lis1 and the dynein motor at the leading pole of neurons. J Neurosci 21:RC187
Estrera, V T; Chen, D T; Luo, W et al. (2001) Signal transduction by the CEACAM1 tumor suppressor. Phosphorylation of serine 503 is required for growth-inhibitory activity. J Biol Chem 276:15547-53
Pu, Y S; Luo, W; Lu, H H et al. (1999) Differential expression of C-CAM cell adhesion molecule in prostate carcinogenesis in a transgenic mouse model. J Urol 162:892-6

Showing the most recent 10 out of 15 publications