Obesity-associated proinflammatory cytokines regulate prostate cancer cell proliferation & migration
XIAOBO WU, M.D., CHRISTINA SHARKEY, M.S., ZONGWEI WANG, Ph.D., ARIA F. OLUMI, M.D..
Beth Israel Deaconess Medical Center HARVARD MEDICAL SCHOOL, BOSTON, MA, USA.
Background Previous studies revealed that obesity is significantly associated with a higher incidence of prostate cancer (PCa). Meanwhile, obesity-associated inflammation plays an important role in tumorigenesis. Here we wished to identify the downstream signaling pathways of obesity-associated proinflammatory cytokines IL-6 and TNF-α effect on prostate cancer cell proliferation and migration.Methods Adipocytes and THP-1 macrophages were differentiated and treated with myristic acid (MA) to induce inflammatory cytokines, and conditioned media (CM) were collected to treat prostate epithelial cancer, androgen-dependent LNCaP and androgen-independent PC-3 cell lines. Cells were also treated with interleukin-6 (IL-6) 10ng/ml, tumor necrosis factor-alpha (TNF-α) 10ng/ml, oncometabolite R-2-hydroxyglutarate 50µM (R-2-HG) and Dutasteride 10µM (SRD5A1 inhibitor). Prostate cancer cell migration and proliferation were assessed by scratch assay (0h, 24h, 48h) and MTT assay (0h, 24h, 48h, 72h) and analyzed by 2-way ANOVA. Enzymes regulating steroid hormone metabolism SRD5A1, AKR1C1, AKR1C3, HSD3B2, CYP17A1 and UGT2B15 were determined by immunocytochemistry and qPCR. The protein level of SRD5A1 was measured by western blot.Results The proliferation of LNCaP and PC-3 cells was significantly stimulated by adding of CM for 24h, 48h, and 72h. The migration of PC-3 cells was also promoted by CM. Addition of testosterone did not change the effect of CM. Administration of IL-6, TNF-α and R-2-HG significantly increased the proliferation and migration of LNCaP and PC-3 cells. IL-6 also increased the expression of SRD5A1.. The expression of AKR1C1 and HSD3B2 was downregulated, and UGT2B15 was upregulated by TNF-α. SRD5A1 was upregulated either by R-2-HG alone or combining with IL-6 and TNF-α, but downregulated by Dutasteride alone.Conclusions Our study suggests that obesity-associated proinflammatory cytokines, IL-6 and TNF-α, affect prostate cancer cells’ proliferation and migration in an androgen-independent manner. Synergistic targeting oncometabolite R-2-HG and proinflammatory cytokines may improve the management of androgen-independent prostate cancer.
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