Department of Urology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan people's hospital), 523059, Dongguan, China.
Department of Urology, Guangdong Medical University, Graduate School, 524002, Zhanjiang, China.
J Transl Med. 2024 May 19;22(1):474. doi: 10.1186/s12967-024-05193-9.
The initiation of fibroblast growth factor 1 (FGF1) expression coincident with the decrease of FGF2 expression is a well-documented event in prostate cancer (PCa) progression. Lactate dehydrogenase A (LDHA) and LDHB are essential metabolic products that promote tumor growth. However, the relationship between FGF1/FGF2 and LDHA/B-mediated glycolysis in PCa progression is not reported. Thus, we aimed to explore whether FGF1/2 could regulate LDHA and LDHB to promote glycolysis and explored the involved signaling pathway in PCa progression.
In vitro studies used RT‒qPCR, Western blot, CCK-8 assays, and flow cytometry to analyze gene and protein expression, cell viability, apoptosis, and cell cycle in PCa cell lines. Glycolysis was assessed by measuring glucose consumption, lactate production, and extracellular acidification rate (ECAR). For in vivo studies, a xenograft mouse model of PCa was established and treated with an FGF pathway inhibitor, and tumor growth was monitored.
FGF1, FGF2, and LDHA were expressed at high levels in PCa cells, while LDHB expression was low. FGF1/2 positively modulated LDHA and negatively modulated LDHB in PCa cells. The depletion of FGF1, FGF2, or LDHA reduced cell proliferation, induced cell cycle arrest, and inhibited glycolysis. LDHB overexpression showed similar inhibitory effect on PCa cells. Mechanistically, we found that FGF1/2 positively regulated STAT1 and STAT1 transcriptionally activated LDHA expression while suppressed LDHB expression. Furthermore, the treatment of an FGF pathway inhibitor suppressed PCa tumor growth in mice.
The FGF pathway facilitates glycolysis by activating LDHA and suppressing LDHB in a STAT1-dependent manner in PCa.
成纤维细胞生长因子 1（FGF1）表达的启动与 FGF2 表达的降低同时发生，这是前列腺癌（PCa）进展的一个有据可查的事件。乳酸脱氢酶 A（LDHA）和 LDHB 是促进肿瘤生长的必需代谢产物。然而，FGF1/FGF2 与 LDHA/B 介导的糖酵解在 PCa 进展中的关系尚未报道。因此，我们旨在探讨 FGF1/2 是否可以调节 LDHA 和 LDHB 以促进糖酵解，并探讨 PCa 进展中涉及的信号通路。
体外研究使用 RT-qPCR、Western blot、CCK-8 测定和流式细胞术分析 PCa 细胞系中的基因和蛋白表达、细胞活力、凋亡和细胞周期。通过测量葡萄糖消耗、乳酸产生和细胞外酸化率（ECAR）来评估糖酵解。对于体内研究，建立了 PCa 的异种移植小鼠模型，并使用 FGF 通路抑制剂进行处理，监测肿瘤生长。
FGF1、FGF2 和 LDHA 在 PCa 细胞中高表达，而 LDHB 表达水平较低。FGF1/2 正向调节 PCa 细胞中的 LDHA，负向调节 LDHB。FGF1、FGF2 或 LDHA 的耗竭减少了细胞增殖，诱导细胞周期停滞，并抑制了糖酵解。LDHB 的过表达对 PCa 细胞也表现出类似的抑制作用。机制上，我们发现 FGF1/2 正向调节 STAT1，STAT1 转录激活 LDHA 的表达，同时抑制 LDHB 的表达。此外，FGF 通路抑制剂的处理抑制了小鼠中 PCa 肿瘤的生长。
FGF 通路通过依赖于 STAT1 的方式正向调节 LDHA 并抑制 LDHB 的表达，从而促进 PCa 中的糖酵解。
