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Structural analysis of the C-CAM1 molecule for its tumor suppression function in human prostate cancer
J T Hsieh1, K Earley, R C Pong
1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Hsieh@utsw.swmed.edu
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.
Insights
The intracellular domain of cell adhesion molecule 1 (C-CAM1) is crucial for inhibiting prostate cancer growth. This finding suggests C-CAM1 interacts with proteins that influence prostate carcinogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Adhesion
Background:
- Diminished cell adhesion molecule 1 (C-CAM1) expression correlates with prostate intraepithelial neoplasia and cancer.
- C-CAM1 expression inhibits prostate cancer growth, suggesting a tumor suppressor role.
- C-CAM1 is a unique cell adhesion molecule with potential signal transduction capabilities.
Purpose of the Study:
- To analyze the functional domains of C-CAM1 responsible for its tumor suppression activity.
- To identify the specific regions within C-CAM1 critical for inhibiting prostate cancer progression.
Main Methods:
- Generated recombinant adenoviruses expressing various C-CAM1 mutants (e.g., AdCAMF488, AdCAMH458, AdCAMG454, AdCAMDeltaD1).
- Characterized viral constructs in vitro.
- Subcutaneously injected infected human prostate cancer cells into athymic mice to assess tumor incidence and volume.
Main Results:
- C-CAM1 mutant lacking cell adhesion function (AdCAMDeltaD1) retained tumor suppression activity.
- C-CAM1 mutants with intracellular domain deletions (AdCAMH458, AdCAMG454) showed reduced or lost tumor suppression activity.
Conclusions:
- The intracellular domain of C-CAM1 is essential for its tumor suppressor function in prostate cancer.
- Interactions involving the C-CAM1 intracellular domain may play a key role in prostate carcinogenesis.