Int J Biol Sci 2021; 17(7):1808-1820. doi:10.7150/ijbs.55919 This issue
1. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou; Chang Gung University College of Medicine, 333, Taoyuan, Taiwan.
2. Department of Oncology‐Pathology, Karolinska Institutet, BioClinicum J6:30, Karolinska University Hospital, SE-17164 Solna, Sweden.
3. Department of Radiation and Medical Oncology, the First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Lane, Wenzhou 325000, Zhejiang, China.
4. Department of Pathology, MacKay Memorial Hospital, Taipei, Taiwan.
5. Department of Surgery and Pancreatic Cancer Team, Chang Gung Memorial Hospital, Linkou; Chang Gung University College of Medicine, 333, Taoyuan, Taiwan.
6. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Increasing evidence reveals that the Rho GTPase-activating protein is a crucial negative regulator of Rho family GTPase involved in tumorigenesis. The Rho GTPase-activating protein 25 (ARHGAP25) has been shown to specifically inactivate the Rho family GTPase Rac1, which plays an important role in pancreatic adenocarcinoma (PAAD) progression. Therefore, here we aimed to clarify the expression and functional role of ARHGAP25 in PAAD. The ARHGAP25 expression was lower in PAAD tissues than that in normal pancreatic tissues based on bioinformatics analysis and immunohistochemistry staining. Overexpression of ARHGAP25 inhibited cell growth of AsPC-1 human pancreatic cancer cells in vitro, while opposite results were observed in BxPC-3 human pancreatic cancer cells with ARHGAP25 knockdown. Consistently, in vivo tumorigenicity assays also confirmed that ARHGAP25 overexpression suppressed tumor growth. Mechanically, overexpression of ARHGAP25 inactivated AKT/mTOR signaling pathway by regulating Rac1/PAK1 signaling, which was in line with the results from the Gene set enrichment analysis on The Cancer Genome Atlas dataset. Furthermore, we found that ARHGAP25 reduced HIF-1α-mediated glycolysis in PAAD cells. Treatment with PF-04691502, a dual PI3K/mTOR inhibitor, hampered the increased cell growth and glycolysis due to ARHGAP25 knockdown in PAAD cells. Altogether, these results conclude that ARHGAP25 acts as a tumor suppressor by inhibiting the AKT/mTOR signaling pathway, which might provide a therapeutic target for PAAD.
Keywords: pancreatic adenocarcinoma, ARHGAP25, AKT/mTOR signaling, glycolysis, proliferation.