Chang Kang-Shuo, Chen Syue-Ting, Lin Wei-Yin, Hsu Shu-Yuan, Sung Hsin-Ching, Lin Yu-Hsiang, Feng Tsui-Hsia, Hou Chen-Pang, Juang Horng-Heng
Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Am J Physiol Cell Physiol. 2025 Feb 1;328(2):C557-C573. doi: 10.1152/ajpcell.00230.2024. Epub 2025 Jan 13.
Hyperglycemia and hyperglycosuria, two primary characteristics of diabetes mellitus, may increase the risk of cancer initiation, particularly for bladder cancer. The effectiveness of metformin, a common antidiabetic agent, is determined by its ability to induce growth differentiation factor 15 (GDF15). However, the mechanism of the GDF15 in relation to glucose, which influences the tumor microenvironment in the human bladder, is not fully understood. This study explores the potential roles of GDF15 in response to glucose in the human bladder. High glucose treatment (30 mM) enhanced phosphorylation of AKT at S473 and AMP-activated protein kinase α1/2 (AMPKα1/2) at S485 to block the counteracting effect of metformin on the AMPK activity in bladder cancer and stroma [human bladder stromal fibroblast (HBdSF) and human bladder smooth muscle cell (HBdSMC)] cells compared with normal glucose treatment (5 mM). Metformin modulated the expressions of GDF15, NDRG1, Maspin, and epithelial-to-mesenchymal transition (EMT) markers to attenuate cell proliferation and invasion of bladder cancer cells. Caffeic acid phenethyl ester (CAPE), like metformin, behaves as an inducer of AMPK activity to stimulate GDF15 expression. Knockdown of GDF15 blocked the downregulation of CAPE on the contraction of HBdSMCs. Both CAPE-induced GDF15 expression and the supernatant from bladder cancer cells with overexpressing GDF15 impeded the HBdSF and HBdSMC migration, suggesting that CAPE-upregulated GDF15 blocked the cell migration. These findings reveal that high glucose treatment inhibits the counteracting effects of either metformin or CAPE on the AMPK activity and GDF15 is downregulated by glucose and induced by metformin and CAPE in both stroma and cancer cells. Furthermore, GDF15 is an antitumor gene facilitating communication between stroma and cancer cells in the human bladder. This study investigates the counteraction of either CAPE or metformin with the AMPK activity increasing GDF15 expression in human bladder cells. The findings are the first study to indicate the secretion of GDF15 from cancer and stroma cells via autocrine or paracrine mechanisms. Our study suggests that GDF15, an antitumor gene in the human bladder induced by AMPK inducers, acts as a communication link between stroma and cancer cells in the human bladder.
高血糖和糖尿是糖尿病的两个主要特征，可能会增加癌症发生的风险，尤其是膀胱癌。二甲双胍是一种常见的抗糖尿病药物，其有效性取决于诱导生长分化因子15（GDF15）的能力。然而，GDF15与葡萄糖相关影响人膀胱肿瘤微环境的机制尚未完全明确。本研究探讨了GDF15在人膀胱中对葡萄糖反应的潜在作用。与正常葡萄糖处理（5 mM）相比，高糖处理（30 mM）增强了AKT在S473位点的磷酸化以及AMP激活的蛋白激酶α1/2（AMPKα1/2）在S485位点的磷酸化，从而阻断了二甲双胍对膀胱癌和基质[人膀胱基质成纤维细胞（HBdSF）和人膀胱平滑肌细胞（HBdSMC）]细胞中AMPK活性的抵消作用。二甲双胍调节GDF15、NDRG1、Maspin和上皮-间质转化（EMT）标志物的表达，以减弱膀胱癌细胞的增殖和侵袭。咖啡酸苯乙酯（CAPE）与二甲双胍一样，作为AMPK活性的诱导剂来刺激GDF15表达。敲低GDF15可阻断CAPE对HBdSMCs收缩的下调作用。CAPE诱导的GDF15表达以及过表达GDF15的膀胱癌细胞的上清液均阻碍了HBdSF和HBdSMC的迁移，这表明CAPE上调的GDF15阻断了细胞迁移。这些发现揭示，高糖处理会抑制二甲双胍或CAPE对AMPK活性的抵消作用，并且GDF15在基质和癌细胞中均被葡萄糖下调，被二甲双胍和CAPE诱导。此外，GDF15是一种抗肿瘤基因，促进人膀胱中基质与癌细胞之间的通讯。本研究调查了CAPE或二甲双胍与增加人膀胱细胞中GDF15表达的AMPK活性之间的相互作用。这些发现是首次表明GDF15通过自分泌或旁分泌机制从癌细胞和基质细胞中分泌的研究。我们的研究表明，GDF15是一种由AMPK诱导剂在人膀胱中诱导产生的抗肿瘤基因，在人膀胱中作为基质与癌细胞之间的通讯纽带。
