title: Zinc stabilizes adenomatous polyposis coli (APC) protein levels and induces cell cycle arrest in colon cancer cells.
abstract: In the present study, we investigated the mechanisms by which zinc causes growth arrest in colon cancer cells. The results suggest that zinc treatment stabilizes the levels of the wild-type adenomatous polyposis coli (APC) protein at the post-translational level since the APC mRNA levels and the promoter activity of the APC gene were decreased in HCT-116 cells (which express the wild-type APC gene) after treatment with ZnCl2. Increased levels of wild-type but not truncated APC proteins were required for the ZnCl2-mediated G2/M phase arrest in different colon cancer cell lines. We further tested whether serum-stimulation, which induces cell cycle arrest in the S phase, can relieve ZnCl2-induced G2/M phase arrest of HCT-116 cells. Results showed that in the HCT-116 cells pretreated with ZnCl2, the serum-stimulation neither changed the distribution of G2/M phase arrested cells nor the increased levels of APC protein. The G2/M phase arrest correlated with retarded growth of HCT-116 cells. To further establish that wild-type APC protein plays a role in ZnCl2-induced G2/M arrest, we treated SW480 colon cancer cells that express truncated APC protein. We found that ZnCl2 treatment did not induce G2/M phase arrest in SW480 cells; however, the cell growth was retarded due to the loss of E-cadherin and alpha-tubulin levels. These results suggest that ZnCl2 inhibits the proliferation of colon cancer cells (which carry the wild-type APC gene) through stabilization of the APC protein and cell cycle arrest in the G2/M phase. On the other hand, ZnCl2 inhibits the proliferation of colon cancer cells (which carry the mutant APC gene) by disrupting cellular attachment and microtubule stability.
authors.affiliation: Department of Anatomy and Cell Biology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Aruna S
authors.initials: AS
authors.lastname: Jaiswal
authors.forename: Satya
authors.initials: S
authors.lastname: Narayan
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016213:Cyclins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044967:Serum; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D017967:Zinc Compounds / Q000494:pharmacology*; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D015820:Cadherins; D002712:Chlorides; D016213:Cyclins; D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D017967:Zinc Compounds; D051176:beta Catenin; C016837:zinc chloride; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases