Oleic acid promotes prostate cancer malignant phenotype via the G protein-coupled receptor FFA1/GPR40
Oleic acid promotes prostate cancer malignant phenotype via the G protein-coupled receptor FFA1/GPR40
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DOI：
10.1002/jcp.26572
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发表时间：
2018-09-01
影响因子：
5.6
通讯作者：
Ulianich, Luca
中科院分区：
文献类型：
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作者：
Liotti, Antonietta;Cosimato, Vincenzo;Ulianich, Luca
前列腺癌(PCa)是男性最常见的恶性肿瘤，也是工业化国家癌症相关死亡的第二大原因。流行病学证据表明，肥胖会促进侵袭性前列腺癌。最近，一个游离脂肪酸(FFA)受体家族被发现并被报道影响肿瘤细胞的几个重要的生物学功能，如增殖、侵袭和凋亡。在此，我们报道了油酸(OA)，一种在人血浆中最普遍的游离脂肪酸，可以促进高度恶性的PC3和DU-145前列腺癌细胞的增殖。此外，通过3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴化法测定，治疗雄激素非依赖性前列腺癌的一线化疗药物多西紫杉醇的细胞毒作用显著降低，这表明这种FFA在化疗耐药中也发挥了作用。通过钙成像技术测量，OA诱导的细胞内钙增加，部分是由于储存操作的钙内流(SOCE)。此外，PI3K/Akt信号通路增强，Akt磷酸化水平增加。有趣的是，减弱FFA1/GPR40的表达可以阻止OA诱导的效应。FFA1/GPR40是包括OA在内的长链FFA的受体。值得注意的是，我们发现FFA1/GPR40在PCa组织中的表达显著高于良性前列腺增生症组织，分别通过实时定量RT-PCR和免疫荧光实验分析。我们的数据表明，OA通过FFA1/GPR40、钙和PI3K/Akt信号通路促进PCa细胞的侵袭性表型。因此，FFA1/GPR40有可能成为预测晚期PCa预后的生物标志物和治疗靶点。
Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death in industrialized countries. Epidemiologic evidence suggests that obesity promotes aggressive PCa. Recently, a family of Free Fatty Acid (FFA) receptors (FFARs) has been identified and reported to affect several crucial biological functions of tumor cells such as proliferation, invasiveness, and apoptosis. Here we report that oleic acid (OA), one of the most prevalent FFA in human plasma, increases proliferation of highly malignant PC3 and DU-145 PCa cells. Furthermore, docetaxel cytotoxic action, the first-line chemotherapeutic agent for the treatment of androgen-independent PCa, was significantly reduced in the presence of OA, when measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, suggesting that this FFA plays also a role in chemoresistance. OA induced intracellular calcium increase, in part due to the store operated calcium entry (SOCE), measured by a calcium imaging technique. Moreover, PI3K/Akt signaling pathway was enhanced, as revealed by increased Akt phosphorylation levels. Intriguingly, attenuating the expression of FFA1/GPR40, a receptor for long chain FFA including OA, prevented the OA-induced effects. Of relevance, we found that FFA1/GPR40 is significantly overexpressed in tissue specimens of PCa, compared to benign prostatic hyperplasia tissues, at both mRNA and protein expression level, analyzed by Real Time RT-PCR and immunofluorescence experiments, respectively. Our data suggest that OA promotes an aggressive phenotype in PCa cells via FFA1/GPR40, calcium and PI3K/Akt signaling. Thus, FFA1/GPR40, might represent a potential useful prognostic biomarker and therapeutic target for the treatment of advanced PCa.