Landim Breno C, de Jesus Mariana M, Bosque Beatriz P, Zanon Renata G, da Silva Claudio V, Góes Rejane M, Ribeiro Daniele L
Department of Cell Biology, Histology and Embriology. Institute of Biomedical Sciences-ICBIM. Federal University of Uberlândia, Brazil.
Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
Prostate. 2018 Jul;78(10):731-742. doi: 10.1002/pros.23517. Epub 2018 Apr 10.
A potential association between obesity and prostate cancer has been proposed. Metformin, an antidiabetes drug, has antiproliferative effects being proposed for cancer treatment. However, under intense proliferative stimulation conditions such as those found in obesity, its efficacy is still uncertain. Thus, we analyzed the effects of saturated fatty acid and/or insulin under high concentrations, with or without metformin, on the proliferation and migration of prostate cells.
Human prostate epithelial cell lines non-tumor (PNT1A) and tumor (PC3) were treated with control media (DMEM, C), palmitate (100 µM, HF), and/or insulin (50 µU, HI) with or without metformin (100 µM) for 24 or 48 h.
Both PNT1A and PC3 cells had greater proliferation when treated with HF, while HI treatment stimulated only PNT1A. Metformin inhibited cell proliferation caused by HF in both cell lines, but it did not block the proliferative action of HI in PNT1A cells. PNT1A increased cell migration after all treatments, while only HF influenced PC3; metformin inhibited the migration stimulated by all obese microenvironments. Both HF and HI treatments in PNT1A and HF treatment in PC3 augmented vimentin expression, resulting in a higher epithelial-mesenchymal transition (which, in turn, could influence cell migration). Metformin inhibited vimentin expression in both normal and tumor cells. Although HF treatment had increased AMPK activation, it also increased the levels of activated ERK1/2, which could be responsible for high cell proliferation in both cell lines. In contrast, HI decreased AMPK activation in both cell lines, whereas it increased ERK1/2 levels in PNT1A and decreased them in PC3 (reflecting greater cell proliferation only in non-tumor cells). Metformin maintained high activation of AMPK and decreased ERK1/2 levels after HF in both cell lines and only after HI in PNT1A, which was able to decrease the cell proliferation triggered by these treatments.
Higher concentrations of palmitate on PC3 cells and palmitate and insulin on PNT1A cells stimulate cellular activities that could favor cancer progression. Metformin inhibited most of these stimuli, showing the efficacy of this drug for cancer adjuvant therapy in obese patients (a group at increased risk for the development of prostrate cancer).
肥胖与前列腺癌之间的潜在关联已被提出。二甲双胍是一种抗糖尿病药物，具有抗增殖作用，被提议用于癌症治疗。然而，在肥胖等强烈增殖刺激条件下，其疗效仍不确定。因此，我们分析了高浓度饱和脂肪酸和/或胰岛素，无论有无二甲双胍，对前列腺细胞增殖和迁移的影响。
用对照培养基（DMEM，C）、棕榈酸（100 μM，HF）和/或胰岛素（50 μU，HI），无论有无二甲双胍（100 μM）处理人前列腺上皮细胞系非肿瘤细胞（PNT1A）和肿瘤细胞（PC3）24或48小时。
用HF处理时，PNT1A和PC3细胞的增殖均增强，而HI处理仅刺激PNT1A细胞增殖。二甲双胍抑制了两种细胞系中由HF引起的细胞增殖，但未阻断HI对PNT1A细胞的增殖作用。所有处理后PNT1A细胞迁移增加，而仅HF影响PC3细胞迁移；二甲双胍抑制了所有肥胖微环境刺激的迁移。PNT1A细胞中的HF和HI处理以及PC3细胞中的HF处理均增加了波形蛋白表达，导致更高的上皮-间质转化（这反过来可能影响细胞迁移）。二甲双胍抑制正常细胞和肿瘤细胞中的波形蛋白表达。尽管HF处理增加了AMPK激活，但它也增加了活化的ERK1/2水平，这可能是两种细胞系中细胞高增殖的原因。相反，HI降低了两种细胞系中的AMPK激活，而它增加了PNT1A细胞中的ERK1/2水平并降低了PC3细胞中的ERK1/2水平（仅反映非肿瘤细胞中的细胞增殖增加）。二甲双胍在两种细胞系中维持了HF处理后AMPK的高激活并降低了ERK1/2水平，在PNT1A细胞中仅在HI处理后维持了这种状态，这能够降低这些处理引发的细胞增殖。
PC3细胞上较高浓度的棕榈酸以及PNT1A细胞上的棕榈酸和胰岛素刺激了可能有利于癌症进展的细胞活动。二甲双胍抑制了大多数这些刺激，表明该药物对肥胖患者（前列腺癌发生风险增加的群体）癌症辅助治疗的疗效。
