Structural analysis of the C-CAM1 molecule for its tumor suppression function in human prostate cancer.
BACKGROUND
Recently, we demonstrated that expression of C-CAM1, an immunoglobulin (Ig)-like cell adhesion molecule (CAM), was diminished in both prostate intraepithelial neoplasia and cancer lesions, indicating that loss of C-CAM1 expression may be involved in the early events of prostate carcinogenesis. Also, increased C-CAM1 expression can effectively inhibit the growth of prostate cancer. Structurally, C-CAM1 represents a unique CAM with a potential signal transducing capability. In this study, we further analyzed the functional domain of C-CAM1 for controlling its tumor suppression function.


METHODS
Recombinant adenoviruses expressing a series of C-CAM1 mutants were generated, such as AdCAMF488 (mutated C-CAM1 containing Tyr-488 --> Phe-488), AdCAMH458 (intracellular domain deletion mutant containing 458 amino acids), AdCAMG454 (intracellular domain deletion mutant containing 454 amino acids), and AdCAMDeltaD1(C-CAM1 mutant containing first Ig domain deletion). After in vitro characterization of each virus, human prostate cancer cells infected with these viruses were subcutaneously injected into athymic mouse. Both tumor incidence and volume were measured for determining the tumor suppression function for each mutant.


RESULTS
In vivo tumorigenic assay indicated that AdCAMDeltaD1 without cell adhesion function still retained its tumor suppression activity. In contrast, both AdCAMH458 and AdCAMG454 decreased or lost their tumor suppression activity.


CONCLUSIONS
Our data indicate that the intracellular domain of the C-CAM1 molecule is critical for inhibiting the growth of prostate cancer, suggesting that C-CAM1 interactive protein(s) may dictate prostate carcinogenesis.
Hsieh
J T
JT
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Hsieh@utsw.swmed.edu
Earley
K
K
Pong
R C
RC
Wang
Y
Y
Van
N T
NT
Lin
S H
SH
D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD; D002272:Carcinoembryonic Antigen; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016147:Genes, Tumor Suppressor / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011487:Protein Conformation; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D010948:Viral Plaque Assay
D015703:Antigens, CD; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; C087701:Ceacam2 protein, mouse; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D000251:Adenosine Triphosphatases