The Upregulation of Caffeic Acid Phenethyl Ester on Growth Differentiation Factor 15 Inhibits Transforming Growth Factor β/Smad Signaling in Bladder Carcinoma Cells

Growth differentiation factor 15 (GDF15) is known as a TGF beta-like cytokine acting on the TGF beta receptor to modulate target genes. GDF15 is regarded as a tumor suppressor gene in the human bladder and the caffeic acid phenethyl ester (CAPE) induces GDF15 expression to inhibit the tumor growth in vitro and in vivo. However, the interactions among GDF15, CAPE, and TGF beta/Smads signaling in the human bladder carcinoma cells remain unexplored. Results revealed that TGF beta downregulated the expression of GDF15 via the activation of Smad 2/3 and Smad 1/5. Induction of GDF15 on its downstream genes, NDRG1 and maspin, is dependent on the TGF beta/Smad pathways. Moreover, TGF beta blocked the CAPE-inducing expressions of GDF15, maspin, and NDRG1. Pretreatment of TGF receptor kinase inhibitor not only blocked the activation of TGF beta but also attenuated the activation of GDF15 on the expressions of maspin and NDRG1. The CAPE treatment attenuated the activation of TGF beta on cell proliferation and invasion. Our findings indicate that TGF beta downregulated the expressions of GDF15, maspin, and NDRG1 via TGF beta/Smad signaling. Whereas, CAPE acts as an antagonist on TGF beta/Smad signaling to block the effect of TGF beta on the GDF15 expression and cell proliferation and invasion in bladder carcinoma cells.