G6PD promotes renal cell carcinoma proliferation through positive feedback regulation of p-STAT3

Abstract

Ectopic Glucose 6-phosphate dehydrogenase (G6PD) expression plays important role in tumor cell metabolic reprogramming and results in poor prognosis of multiple malignancies. Our previous study indicated that G6PD is overexpressed in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC. However, its role in RCC is still unclear. Here, we demonstrate that G6PD is not only up-regulated in all types of RCC specimens but also displays higher activities in RCC cell lines. G6PD overexpression promoted RCC cell proliferation, altered cell cycle distribution, and enhanced xenografted RCC development. G6PD up-regulated ROS generation by facilitating NADPH-dependent NOX4 activation, which led to increased expression of p-STAT3 and CyclinD1. Enhanced ROS generation rescued the p-STAT3 and CyclinD1 expression reduction in G6PD-knockdown cells, while ROS scavengers reversed the up-regulated p-STAT3 and CyclinD1 expression in G6PD-overexpressing cells. Furthermore, p-STAT3 activated G6PD gene expression via binding to the G6PD promoter, demonstrating that p-STAT3 forms a positive feedback regulatory loop for G6PD overexpression. G6PD expression was up or down-regulated in response to the impact of p-STAT3 activators or inhibitors. Therefore, G6PD may be an effective RCC therapeutic target.

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

“…It has been reported that G6PD serves key roles in reactive oxygen species (ROS) accumulation. Previous results from our laboratory demonstrated that G6PD could promote ROS generation by increasing NADPH oxidase 4 activity in ccRCC (16). Furthermore, increased oxidative stress is an important factor leading to abnormal intracellular signal transduction (17,18).…”

“…Furthermore, G6PD can cooperate with numerous signaling pathways in order to promote cancer, and G6PD was reported to be overexpressed in various types of tumor, including breast carcinoma, ccRCC and lung adenocarcinoma (13)(14)(15). Previous work from our laboratory described the prognostic significance of G6PD in ccRCC, and demonstrated its role in promoting tumor growth through positive feedback regulation of phospho-signal transducer and activator of transcription 3 (p-STAT3) (14,16). However, G6PD ability to promote ccRCC invasion remains unknown.…”

“…Furthermore, increased oxidative stress is an important factor leading to abnormal intracellular signal transduction (17,18). ROS can induce continuous activation of pSTAT3, NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways (16,(19)(20)(21)(22)(23)(24) and promote the growth of certain cancer, including ccRCC, melanoma and liver cancer, regulate angiogenesis, and accelerate tumor metastasis by promoting the expression of a series of proliferation-and metastasis-related genes, including cyclinD1 and matrix metalloproteinases (MMPs) (16,(25)(26)(27).…”

“…To do so, the underlying mechanisms of G6PD in ccRCC invasion, and the association between G6PD expression, MMPs expression and ROS-MAPK signaling pathway were investigated. Cells were transfected in order to knockdown or overexpress G6PD as previously described (16). To construct G6PD-knocked down Caki-1 stable cells, 2x10 5 Caki-1 cells were seeded in a 6-well plate.…”

“…no. sc-203336) was purchased from Santa Cruz Biotechnology, Inc. 786-O cells were treated with NAC (20 mM) for 24 h or H 2 O 2 (1 mM) for 2 h (16). The MAPK signaling pathway inhibitors SP600125 (cat.…”