(P13-047-23) Estrogenic Protection Against Colorectal Cancer Development in Obesity

Objectives: Colorectal cancer (CRC) is one of the most common types of cancer diagnosed in men and women. While obesity is a prominent CRC risk factor in both sexes, the association is stronger in men than in women. The prevalence of obesity is higher in women than in men among all age groups; however, men have higher incidences of CRC than women. Thus, the present study aims to understand the protective effects of estrogen against obesity-associated CRC and the underlying mechanisms of action at cellular and metabolic levels.

Methods: HCT116 human CRC cells were treated with leptin and/or 17 β-estradiol (E2, the most potent physiological estrogen). Cell number, cell proliferation, and apoptosis were measured after 48 hours using a cell counter, BrdU assay, and cleaved-caspase 3/7 activation of ApoTox-Glo™ triplex assay, respectively. Moreover, metabolic profiles were determined using HPLC-MS targeted metabolic profiling.

Results: Treatment of physiological dose of E2 (10 nM) significantly diminished leptin-stimulated growth of HCT116 cells. Leptin at 100 and 1,000 ng/ml induced cell proliferation without affecting apoptosis. Importantly, E2 dose-dependently attenuated leptin-stimulated CRC cell proliferation, with E2 at 10 nM attenuated proliferation without inducing cell apoptosis. Estrogen regulates metabolic functions via targeting the mitochondria to sustain energetic demands in many types of cells. We found that levels of the top 10 detected targeted metabolites, including energy metabolites (e.g., ATP and flavin adenine dinucleotide [FAD]) and amino acid metabolites (e.g., glycine and proline), were greater in E2-treated cells compared to the control, demonstrating that E2 induced a metabolic shift in leptin-stimulated HCT116 cells.

Conclusions: Our results demonstrated for the first time that estrogen at a physiological concentration suppressed leptin-induced cell growth via inhibiting cell proliferation and altering metabolic regulation in HCT116 human CRC cells. A follow-up animal study employing an improved mouse model of obesity-associated CRC is underway, which will help to further understand the role of estrogen in CRC development in the setting of obesity.

Funding Sources: Miami University's College of Education, Health, and Society Interdisciplinary Research Seed Grant and a grant from Miami University Committee on Faculty Research.