Leptin activates MAPK signaling in human breast and prostate cancer

Abstract

Introduction: Obesity is associated with an increased risk of developing cancer. Leptin is a 16 kD peptide hormone secreted by adipose tissue with higher circulating concentrations reported in obese people. In addition, recent studies indicate that leptin is mitogenic, as well as pro-angiogenic, in reproductive tissues. We have demonstrated that exogenous leptin leads to increased proliferation of breast and prostate cancer cells in vitro. However, the mechanism behind this effect is unknown. We hypothesized that increased cancer cell proliferation in response to leptin occurs via alterations in mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) signal transduction pathways. Methods: Two cancer cell lines, ZR-75 (breast) and DU145 (prostate), were cultured using standard techniques. Cells were treated with human recombinant leptin (40 ng/ml) for 48 h. This dose of leptin simulates circulating levels in obese humans. After treatment, cells were harvested and analyzed via immunoblot for Akt and ERK phosphorylation, measures of PI3K and MAPK activity respectively. Results: Western blot analysis revealed that PI3K activity was not altered by leptin stimulation in either cell line tested. However, after treatment, ERK phosphorylation was increased in both the ZR-75 (approximately 4-fold) and DU145 (approximately 2-fold) cell lines, indicating an angiogenic response to leptin exposure. Conclusions: These preliminary results indicate that MAPK activation may play an important role in leptin-induced cancer cell proliferation. Moreover, it suggests that high levels of circulating leptin could act in vivo as a growth factor in the progression of breast and prostate cancers, thus establishing a link between the risk of obesity and carcinogenesis.