期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 17, 期 7, 页码 1808-1820出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.55919
关键词
pancreatic adenocarcinoma; ARHGAP25; AKT; mTOR signaling; glycolysis; proliferation
资金
- Ministry of Science and Technology [MOST 108-2314-B-182A-063]
- Chang Gung Memorial Hospital [CMRPG3K1721]
ARHGAP25 acts as a tumor suppressor in pancreatic adenocarcinoma by inhibiting the AKT/mTOR signaling pathway. Its overexpression can suppress tumor growth by regulating Rac1/PAK1 signaling, as shown in both in vitro and in vivo experiments. Furthermore, ARHGAP25 reduces HIF-1 alpha-mediated glycolysis in PAAD cells, suggesting it as a potential therapeutic target for PAAD.
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-1 alpha-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.
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