Growth differentiation factor 15 is a glucose-downregulated gene acting as the cross talk between stroma and cancer cells of the human bladder.

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.