Extracellular zinc stabilizes adenomatous polyposis coli (APC) protein levels and induces cell cycle arrest in colon cancer cells. Free

3022

Zinc is required for the normal functioning of a large number of enzymes, and it is a structural component of many proteins, including hormones, neuropeptides, and receptors. Zinc deficiency has a profound adverse effect on cellular biochemistry and is recognized as a world-wide public health problem. Previous studies have indicated that zinc deficiency is one of the primary risk factors in the development of colorectal carcinogenesis. Thus, supplementation of zinc can prevent colorectal carcinogenesis in the high risk populations. In the present study, we investigated the mechanisms by which zinc may cause 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 APC gene’s promoter activity were decreased in HCT-116 cells after treatment with ZnCl₂. Increased levels of the wild-type APC protein were required for the ZnCl₂-mediated G₂/M phase arrest in HCT-116 colon cancer cells. 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 which 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, which was due to the loss of E-cadherin and α-tubulin levels. Our results suggest that ZnCl₂ inhibits the proliferation of colon cancer cells (carrying 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 (carrying mutant APC gene) by disrupting cell-cell communication and microtubule stability.