Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, the Second Affiliated Hospital of South China University of Technology, Guangzhou, China.
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas.
Cancer Res. 2018 Aug 15;78(16):4459-4470. doi: 10.1158/0008-5472.CAN-17-3226. Epub 2018 Jun 11.
The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression. FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer. http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg .
在前列腺癌的进展过程中，异位成纤维细胞生长因子受体 1（FGFR1）的表达获得得到了充分的证明。尽管它赋予了生长优势并促进了细胞存活，但它如何促进前列腺癌的进展尚不完全清楚。在这里，我们报告 FGFR1 酪氨酸激酶通过调节乳酸脱氢酶（LDH）同工酶的表达来重新编程前列腺癌细胞的能量代谢。FGFR1 通过酪氨酸磷酸化增加 LDHA 的稳定性，并通过促进其启动子甲基化降低 LDHB 的表达，从而将细胞代谢从氧化磷酸化转向有氧糖酵解。LDHA 耗竭会损害，而 LDHB 耗竭会增强前列腺癌细胞的致瘤性。此外，FGFR1 过表达和异常 LDH 同工酶表达与前列腺癌患者的总生存时间和生化复发时间较短有关。我们的研究结果表明，异位 FGFR1 表达重新编程了前列腺癌细胞的能量代谢，这是前列腺癌进展中的一个标志性变化。FGF 信号通过差异调节 LDHA 和 LDHB 驱动了瓦伯格效应，从而促进了前列腺癌的进展。http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg 。
