Retinol inhibits the growth and invasion of all-trans-retinoic acid resistant colon cancer in vitro and in vivo

Colorectal cancer is the third most common cancer and cause of death due to cancer in the United States. Death due to colorectal cancer is generally caused by hepatic metastasis rather than the primary tumor itself. The five-year survival rate is only 10% for patients whose colorectal cancer metastasized, which indicates the need for more effective therapies to treat colon cancer. The diet contains (1) preformed vitamin A as retinyl esters in animal-derived food sources and (2) provitamin A carotenoids in plant-derived food sources. Once absorbed, retinol is re-esterified and transported to the liver, the major site of vitamin A storage. Therefore, dietary vitamin A supplementation can increase retinol levels in the colon and liver, potentially affecting both primary colon tumors and liver metastases of the primary tumors. All-trans--retinoic acid (ATRA) is thought to regulate most of the effects of retinoids, via the ATRA/RAR/RARE pathway exerting an inhibitory effect on cancer growth and progression. As cancer progresses, colon cancer acquires the resistance to ATRA. The purpose of this study is to understand the mechanism by which retinol decreased the growth and progression of ATRA-resistant human colon cancer in vivo and in vitro. We first demonstrated that retinol decreased the growth of ATRA-resistant colon cancer cells by arresting cell cycle progression independent of the ATRA/RAR/RARE pathway. Next, we showed retinol inhibited ATRA-resistant human colon cancer cell invasion by decreasing MMP-2, -9 and PI3K activity in vitro. Finally, dietary vitamin A supplementation decreased the incidence and multiplicity of liver metastases in nude mice intrasplenically injected with ATRA-resistant human colon cancer cells. Taken together, these data suggest the possibility of dietary vitamin A supplementation for colon cancer therapy and prevention.