The Adipocyte-Derived Hormone Leptin Has Proliferative Actions on Androgen-Resistant Prostate Cancer Cells Linking Obesity to Advanced Stages of Prostate Cancer
Background. Because obesity may be a risk factor for prostate cancer, we investigated proliferative effects of adipocytes-derived hormone leptin on human prostate cancer cells and assessed the role of mitogen-activated protein kinase (MAPK) signaling pathway in mediating these actions. Material and Methods. Three human prostate cancer cell lines were treated with increasing doses of recombinant leptin. Cell growth was measured under serum-free conditions using a spectrophotometric assay. Further, Western blotting was applied to detect the phosphorylation of an ERK1/2, and a specific inhibitor of MAPK (PD98059; 40？μM) was used. Results. In both androgen-resistant cell lines DU145 and PC-3, cell growth was dose-dependently increased by leptin after 24 hrs and 48 hrs of incubation, whereas leptin’s proliferative effects on androgen-sensitive cell line LNCaP was less pronounced. Further, leptin caused dose-dependent ERK1/2 phosphorylation in both androgen-resistant cell lines, and pretreatment of these cells with PD98059 inhibited these responses. Conclusions. Leptin may be a potential link between obesity and risk of progression of prostate cancer. Thus, studies on leptin and obesity association to prostate cancer should differentiate patients according to androgen sensitivity. 1. Introduction Among other serious diseases, obesity is known to be associated with an increased risk for a number of different cancers such as breast cancer, esophageal cancer, colon cancer, renal cell cancer, and pancreatic cancer [1, 2]. Studies using body fat measurement and disease stratification according to prostate cancer (PCa) stage have found a strong association between obesity and PCa [3–5]. In Western population with high fat intake and prevalence of obesity, the incidence of clinically significant prostate cancer and disease-specific mortality rates are increasing [3]. Meanwhile, increased levels of endogenous hormones associated with overweight and obesity, such as sex steroids, insulin, insulin-like growth factor I, and leptin, have been described as potential mechanisms linking obesity to prostate cancer [1]. In particular, the fat hormone leptin has been shown to be positively associated with prostate cancer [6–9]. Recently, there has been an increasing interest on the study of cellular and molecular mechanism of cancer by energy restriction models [10]. For instance, Berrigan et al. and Mai et al. observed that the relationship between energetic balance and cancer development could be explained to a great extent by caloric restriction, as mediated through leptin
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