ARHGAP40 suppresses clear cell renal cell carcinoma progression and is associated with altered glutamine-related metabolism and redox balance.
6 affiliations
- 1School of Biology and Biological Engineering, South China University of Technology, Guangzhou, People's Republic of China.
- 2Guangzhou Huayin Medical Laboratory Center Co, Ltd, Guangzhou, People's Republic of China.
- 3Guangzhou Huayin Health Group Co., Ltd, Guangzhou, People's Republic of China.
- 4Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People's Republic of China.
- 5Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People's Republic of China.
- 6School of Life Sciences, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing, People's Republic of China.
Abstract
Objective
Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular and metabolic heterogeneity. This study investigated the functional role of ARHGAP40 in ccRCC and examined signaling and metabolic changes associated with ARHGAP40 expression.Methods
TCGA-KIRC and DiseaseMeth datasets were used to analyze ARHGAP40 expression and promoter methylation. Gain- and loss-of-function experiments evaluated malignant phenotypes in vitro, and an ARHGAP40-overexpression xenograft model was used to assess tumor growth. Co-immunoprecipitation and RhoA activity assays assessed ARHGAP40-RhoA interaction and RhoA activation, while PI3K/AKT signaling, glutamine metabolism, GSH/GSSG, and ROS levels were examined. Rescue experiments were performed using SC79, RhoA-Q63L, and NAC.Results
ARHGAP40 was downregulated in ccRCC and was associated with increased promoter methylation. ARHGAP40 overexpression suppressed cell proliferation, migration, invasion, EMT, and xenograft growth, while promoting apoptosis and G1-phase arrest; ARHGAP40 knockdown produced the opposite effects. Mechanistically, ARHGAP40 was associated with RhoA, and its overexpression was accompanied by reduced RhoA activity and PI3K/AKT phosphorylation. ARHGAP40 overexpression also reduced intracellular glutamine and glutamate levels and net glutamine consumption, decreased the GSH/GSSG ratio, and increased ROS levels. SC79 and RhoA-Q63L partially reversed the biological and redox effects induced by ARHGAP40 overexpression, whereas NAC reversed the redox changes.Conclusion
ARHGAP40 acts as a tumor suppressor in ccRCC. Our findings support a functional link between ARHGAP40, RhoA-PI3K/AKT signaling, glutamine-related metabolism, and cellular redox balance.
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BibTeX
@article{you2026arhgap40,
title = {{ARHGAP40 suppresses clear cell renal cell carcinoma progression and is associated with altered glutamine-related metabolism and redox balance.}},
author = {Na You and Xiaoxia Wang and Caizhu Wang and Long Ma and Yanli Lyu and Han Liu and Fan Yang and Jiandong Wang and Longjiang Zhang and Jufang Wang},
journal = {Cancer biology \& therapy},
year = {2026},
month = oct,
doi = {10.1080/15384047.2026.2746137},
url = {https://europepmc.org/article/MED/42848714},
note = {CC BY},
}
RIS
TY - JOUR
TI - ARHGAP40 suppresses clear cell renal cell carcinoma progression and is associated with altered glutamine-related metabolism and redox balance.
AU - Na You
AU - Xiaoxia Wang
AU - Caizhu Wang
AU - Long Ma
AU - Yanli Lyu
AU - Han Liu
AU - Fan Yang
AU - Jiandong Wang
AU - Longjiang Zhang
AU - Jufang Wang
PY - 2026
DA - 2026/10/08
JO - Cancer biology & therapy
DO - 10.1080/15384047.2026.2746137
UR - https://europepmc.org/article/MED/42848714
AB - Objective Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular and metabolic heterogeneity. This study investigated the functional role of ARHGAP40 in ccRCC and examined signaling and metabolic changes associated with ARHGAP40 expression.Methods TCGA-KIRC and DiseaseMeth datasets were used to analyze ARHGAP40 expression and promoter methylation. Gain- and loss-of-function experiments evaluated malignant phenotypes in vitro, and an ARHGAP40-overexpression xenograft model was used to assess tumor growth. Co-immunoprecipitation and RhoA activity assays assessed ARHGAP40-RhoA interaction and RhoA activation, while PI3K/AKT signaling, glutamine metabolism, GSH/GSSG, and ROS levels were examined. Rescue experiments were performed using SC79, RhoA-Q63L, and NAC.Results ARHGAP40 was downregulated in ccRCC and was associated with increased promoter methylation. ARHGAP40 overexpression suppressed cell proliferation, migration, invasion, EMT, and xenograft growth, while promoting apoptosis and G1-phase arrest; ARHGAP40 knockdown produced the opposite effects. Mechanistically, ARHGAP40 was associated with RhoA, and its overexpression was accompanied by reduced RhoA activity and PI3K/AKT phosphorylation. ARHGAP40 overexpression also reduced intracellular glutamine and glutamate levels and net glutamine consumption, decreased the GSH/GSSG ratio, and increased ROS levels. SC79 and RhoA-Q63L partially reversed the biological and redox effects induced by ARHGAP40 overexpression, whereas NAC reversed the redox changes.Conclusion ARHGAP40 acts as a tumor suppressor in ccRCC. Our findings support a functional link between ARHGAP40, RhoA-PI3K/AKT signaling, glutamine-related metabolism, and cellular redox balance.
SN - 1538-4047
SN - 1555-8576
ER -