ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway

Huang, Wen‐Shih; Chen, Yi; Su, Huafang; Chen, Tung-Ying; Gao, Jiwei; Liu, Yaxuan; Yeh, Chun‐Nan; Li, Shuijie

doi:10.7150/ijbs.55919

Cited by 21 publications

(18 citation statements)

References 32 publications

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“…For example, Wang et al revealed that Arbutin treatment inhibited OSa cell proliferation and metastasis by downregulating MTHFD1L via miR-338-3p and inactivating the AKT/mTOR signaling [ 46 ]. Huang et al discovered that ARHGAP25-mediated inactivation of AKT/mTOR signaling impaired tumor growth and glycolysis in pancreatic adenocarcinoma [ 47 ]. Wu et al uncovered that Deoxyshikonin inactivated the AKT/mTOR signaling to inhibit cell viability and glycolysis in acute myeloid leukemia [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

S100 calcium-binding protein A10 contributes to malignant traits in osteosarcoma cells by regulating glycolytic metabolism via the AKT/mTOR pathway

2022

Bioengineered

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As an aggressive musculoskeletal malignancy, osteosarcoma (OSa) is popular among young adults and teenagers worldwide. S100 calcium-binding protein A10 (S100A10) functioned as a novel tumor-promoting protein in several human cancers. However, its role in OSa remains obscure. In this study, gene and protein levels were respectively determined by RT-qPCR or Western blotting. OSa cell proliferation, apoptosis, and metastasis were evaluated via CCK-8, colony formation, flow cytometry, and Transwell assays. To assess the glycolysis level, glucose consumption and lactate production were detected. It was found S100A10 was highly expressed in OSa tissues and cell lines. Besides, S100A10 facilitated proliferation and metastasis, and inhibited apoptosis in OSa cells. In addition, S100A10 regulated OSa cell proliferation, metastasis and apoptosis via mediating the glycolysis process. Furthermore, S100A10-mediated AKT/mTOR signaling accelerated glycolysis, thereby promoting malignant behaviors in OSa cells. Taken together, our findings indicated that S100A10 might promote malignant phenotypes of OSa cells by accelerating glycolysis and activating the AKT/mTOR signaling, providing a promising target for OSa treatment.

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Section: Discussionmentioning

confidence: 99%

S100 calcium-binding protein A10 contributes to malignant traits in osteosarcoma cells by regulating glycolytic metabolism via the AKT/mTOR pathway

2022

Bioengineered

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“…Knockdown of ARHGAP15 resulted in activation of PAK1/2 and indirectly promoted Rac activation, thereby enhancing cancer-promoting signal transduction 25 . Other RhoGAPs, such as ARHGAP4, ARHGAP6, ARHGAP9, ARHGAP12 and ARHGAP25, have also demonstrated tumor suppressor roles in different types of tumors 26 - 30 . However, no study has systematically investigated the clinical significance of RhoGAPs and analyzed the functions of significant molecules in HCC.…”

Section: Discussionmentioning

confidence: 99%

ARHGAP24 represses β-catenin transactivation-induced invasiveness in hepatocellular carcinoma mainly by acting as a GTPase-independent scaffold

Yang¹,

Wang²,

Qian³

et al. 2022

Theranostics

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Rationale: Accumulating evidence shows that Rho-GTPase-activating proteins (RhoGAPs) exert suppressive roles in cancer cell proliferation and metastasis. However, no study has systematically investigated the clinical significance of RhoGAPs and analyzed the functions of ARHGAP24 in hepatocellular carcinoma (HCC). Methods: The relationship between RhoGAP expression and HCC prognosis was investigated via using The Cancer Genome Atlas and Gene Expression Omnibus databases. ARHGAP24 expression was detected by reverse transcription-polymerase chain reaction, western blot and immunohistochemistry staining assays. Moreover, in vitro assays including cell counting kit-8, colony formation, wound healing and Transwell assays, and in vivo tumor growth and pulmonary metastases evaluations were conducted to evaluate the biological function of ARHGAP24 in HCC. Liquid chromatography-tandem mass spectrometry, co-immunoprecipitation, GTPase activation, ubiquitination, and luciferase reporter assays and bioinformatics analysis were carried out to gain insights into the mechanisms underlying the tumor-suppressive function of ARHGAP24. Results: ARHGAP24 expression was dramatically decreased in HCC tissues, and low ARHGAP24 expression was an independent poor prognostic indicator for progression-free survival in HCC patients. ARHGAP24 overexpression significantly inhibited cell proliferation, migration and invasion, while knockdown of ARHGAP24 exerted the opposite effects. Through Gene Set Enrichment Analysis (GSEA), we found ARHGAP24 mainly suppressed HCC cell proliferation and invasion by attenuating β-catenin transactivation and blocking β-catenin signaling could effectively abolish the promotional effects of ARHGAP24 knockdown in HCC cells. Notably, GAP-deficient mutant of ARHGAP24 exerted similar inhibitory effects as the wild-type did, indicating suppressive function of ARHGAP24 was independent of its RhoGAP activity. Moreover, we identified pyruvate kinase M2 (PKM2) as a new binding partner of ARHGAP24, which recruited a novel E3 ligase (WWP1) and subsequently promoted PKM2 degradation. WWP1 knockdown significantly reduced the inhibitory function of ARHGAP24, and the C-terminal fragments of ARHGAP24 (amino acids 329 - 430 and 631 - 748) bound directly to WWP1 and PKM2 (amino acids 388 - 531), respectively. Conclusions: Our data indicate that ARHGAP24 may be an independent prognostic indicator for HCC. It is a critical suppressor of HCC that recruits WWP1 for PKM2 degradation. Targeting the ARHGAP24/WWP1/PKM2/β-catenin axis may provide new insights into HCC prevention and treatment.

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“…The PI3K/AKT/mTOR pathway is implicated in glycolysis and promotes PC growth (Hu et al 2019 ). ARHGAP25 suppresses the growth of PC cells by inhibiting glycolysis via the AKT/mTOR pathway (Huang et al 2021 ). TRIM59 is reported to promote PC progression through the PI3K/AKT/mTOR-glycolysis signaling axis (Li et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

CXCL12 secreted by pancreatic stellate cells accelerates gemcitabine resistance of pancreatic cancer by enhancing glycolytic reprogramming

Cao

et al. 2022

Animal Cells and Systems

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Pancreatic stellate cells (PSCs) are the primary cell components of pancreatic cancer (PC) and are involved in tumor growth, metastasis and resistance. However, the role and the mechanism of PSCs in gemcitabine (GEM) resistance to PC still need more investigation. We found that CXCL12 mRNA and secreted CXCL12 protein were higher in PSCs after GEM treatment. The conditioned medium (CM) from GEM-treated PSCs reduced the GEM sensitivity of PC cells. Blocking of CXCL12 in CM by anti-CXCL12 antibody partly restored the GEM sensitivity of PC cells. Blocking of CXCL12 decreased glucose consumption, lactate production, ECAR, and glycolysis-related gene expression in PC cells. The PI3K/AKT/mTOR pathway was activated by the binding of CXCL12 and CXCR4. Moreover, CXCR4 mRNA and protein expressions in PC cells were increased after GEM treatment. Our results indicated the cross-talk between PSCs and PC cells during GEM chemotherapy. CXCL12 secreted by PSCs reduces GEM sensitivity of PC cells by binding to CXCR4 and activating PI3K/AKT/mTOR-glycolysis pathway in PC. Our findings would lay the foundation for solving GEM resistance in PC.

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ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway

Cited by 21 publications

References 32 publications

S100 calcium-binding protein A10 contributes to malignant traits in osteosarcoma cells by regulating glycolytic metabolism via the AKT/mTOR pathway

S100 calcium-binding protein A10 contributes to malignant traits in osteosarcoma cells by regulating glycolytic metabolism via the AKT/mTOR pathway

ARHGAP24 represses β-catenin transactivation-induced invasiveness in hepatocellular carcinoma mainly by acting as a GTPase-independent scaffold

CXCL12 secreted by pancreatic stellate cells accelerates gemcitabine resistance of pancreatic cancer by enhancing glycolytic reprogramming

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