ARHGAP4 Mediates the Warburg Effect in Pancreatic Cancer Through the MTOR and HIF-1α Signaling Pathways

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2019 Jul 16

PMID 31303760

Citations 25

Authors

Yehua Shen

Gang Chen

Liping Zhuang

Litao Xu

Junhua Lin

Luming Liu

Affiliations

Soon will be listed here.

Abstract

Objective: The phenomenon that cancer cells avidly exhibit glycolysis with lactate secretion and decrease in mitochondrial activity under aerobic conditions is known historically as the Warburg effect. Rho GTPase-activating protein 4 (ARHGAP4) is an important negative regulator of the Rho signaling pathway that was associated with the tumorigenesis. Our study aims to determine the function of ARHGAP4 in controlling the glycolytic process of pancreatic cancer in vitro and possible molecular mechanism involved.

Methods: ARHGAP4 and PKM2 expressions in pancreatic cancer tissues were measured by immunohistochemistry. Human pancreatic cancer cells transfected with ARHGAP4 expressing lentivirus or siRNA were treated with either mTOR inhibitor (Rapamycin) or HIF-1α inhibitor (YC-1), and the effects were analyzed on cell viability, glucose uptake, lactate release, and the levels of ARHGAP4, p-mTOR, mTOR, PKM2, and HIF-1α expression.

Results: Our findings showed that ARHGAP4 and PKM2 expressions were, respectively, down-regulated and up-regulated in pancreatic cancer tissues. Overexpression of ARHGAP4 significantly inhibited cell viability, glucose uptake, lactate release, PKM2 expression, and activation of mTOR and HIF-1α signaling pathways in pancreatic cancer cells while ARHGAP4 silencing and treatment of Rapamycin or YC-1 showed inverse effects. Additionally, ARHGAP4 downregulation induced cell morphology of pancreatic cancer was inhibited by Rapamycin or YC-1 treatment.

Conclusion: These findings suggest that mTOR and HIF-1α signaling pathways can regulate the ARHGAP4-mediated glycolytic process of pancreatic cancer.

Citing Articles

The role of hypoxic microenvironment in autoimmune diseases.

Gong X, Yang S, Wang Z, Tang M Front Immunol. 2024; 15:1435306.

PMID: 39575238 PMC: 11578973. DOI: 10.3389/fimmu.2024.1435306.

Progression of mA in the tumor microenvironment: hypoxia, immune and metabolic reprogramming.

Han X, Zhu Y, Ke J, Zhai Y, Huang M, Zhang X Cell Death Discov. 2024; 10(1):331.

PMID: 39033180 PMC: 11271487. DOI: 10.1038/s41420-024-02092-2.

Inhibits Proliferation and Growth of SW620 Colon Cancer Cells by Cell Cycle and Differentiation Pathways.

Fu M, Pan S, Cai X, Lv C, Pan Q Scientifica (Cairo). 2024; 2024:5791613.

PMID: 38938545 PMC: 11208814. DOI: 10.1155/2024/5791613.

Rho GTPase-activating protein 4 is upregulated in Kidney Renal Clear Cell Carcinoma and associated with poor prognosis and immune infiltration.

Xiao X, Lv X, Lin T, Li J, Wang R, Tian S Cancer Biomark. 2024; 40(2):205-223.

PMID: 38905034 PMC: 11307029. DOI: 10.3233/CBM-230388.

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.

Syed F, Ballew O, Lee C, Rana J, Krishnan P, Castela A bioRxiv. 2024; .

PMID: 38766166 PMC: 11100605. DOI: 10.1101/2024.03.20.585925.

References

Katoh Y, Katoh M . Identification and characterization of ARHGAP27 gene in silico. Int J Mol Med. 2004; 14(5):943-7. View

Chen Z, Lu W, Garcia-Prieto C, Huang P . The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr. 2007; 39(3):267-74. DOI: 10.1007/s10863-007-9086-x. View

Vogt D, Gray C, Young 3rd W, Orellana S, Malouf A . ARHGAP4 is a novel RhoGAP that mediates inhibition of cell motility and axon outgrowth. Mol Cell Neurosci. 2007; 36(3):332-42. PMC: 2111057. DOI: 10.1016/j.mcn.2007.07.004. View

Mazurek S . Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 2010; 43(7):969-80. DOI: 10.1016/j.biocel.2010.02.005. View

Vander Heiden M, Locasale J, Swanson K, Sharfi H, Heffron G, Amador-Noguez D . Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010; 329(5998):1492-9. PMC: 3030121. DOI: 10.1126/science.1188015. View

Koppenol W, Bounds P, Dang C . Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011; 11(5):325-37. DOI: 10.1038/nrc3038. View

Luo W, Semenza G . Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget. 2011; 2(7):551-6. PMC: 3248177. DOI: 10.18632/oncotarget.299. View

Yang X, Zhong X, Tanyi J, Shen J, Xu C, Gao P . mir-30d Regulates multiple genes in the autophagy pathway and impairs autophagy process in human cancer cells. Biochem Biophys Res Commun. 2013; 431(3):617-22. PMC: 3578012. DOI: 10.1016/j.bbrc.2012.12.083. View

Paulson A, Tran Cao H, Tempero M, Lowy A . Therapeutic advances in pancreatic cancer. Gastroenterology. 2013; 144(6):1316-26. DOI: 10.1053/j.gastro.2013.01.078. View

10.

Li W, Wang J, Chen Q, Qian X, Li Q, Yin Y . Insulin promotes glucose consumption via regulation of miR-99a/mTOR/PKM2 pathway. PLoS One. 2013; 8(6):e64924. PMC: 3677911. DOI: 10.1371/journal.pone.0064924. View

11.

Iqbal M, Siddiqui F, Gupta V, Chattopadhyay S, Gopinath P, Kumar B . Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer. 2013; 12:72. PMC: 3710280. DOI: 10.1186/1476-4598-12-72. View

12.

Wolfgang C, Herman J, Laheru D, Klein A, Erdek M, Fishman E . Recent progress in pancreatic cancer. CA Cancer J Clin. 2013; 63(5):318-48. PMC: 3769458. DOI: 10.3322/caac.21190. View

13.

Ganapathy-Kanniappan S, Geschwind J . Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013; 12:152. PMC: 4223729. DOI: 10.1186/1476-4598-12-152. View

14.

Ryan D, Hong T, Bardeesy N . Pancreatic adenocarcinoma. N Engl J Med. 2014; 371(11):1039-49. DOI: 10.1056/NEJMra1404198. View

15.

Cheng S, Quintin J, Cramer R, Shepardson K, Saeed S, Kumar V . mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014; 345(6204):1250684. PMC: 4226238. DOI: 10.1126/science.1250684. View

16.

Yang J, Kalim K, Li Y, Zhang S, Hinge A, Filippi M . RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. J Allergy Clin Immunol. 2015; 137(1):231-245.e4. PMC: 4684821. DOI: 10.1016/j.jaci.2015.05.004. View

17.

Woo Y, Shin Y, Lee E, Lee S, Jeong S, Kong H . Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells. PLoS One. 2015; 10(7):e0132285. PMC: 4497721. DOI: 10.1371/journal.pone.0132285. View

18.

Lin Q, Yang F, Jin C, Fu D . Current status and progress of pancreatic cancer in China. World J Gastroenterol. 2015; 21(26):7988-8003. PMC: 4499341. DOI: 10.3748/wjg.v21.i26.7988. View

19.

Li J, Liu Y, Yin Y . Inhibitory effects of Arhgap6 on cervical carcinoma cells. Tumour Biol. 2015; 37(2):1411-25. DOI: 10.1007/s13277-015-4502-z. View

20.

Mohammad G, Olde Damink S, Malago M, Dhar D, Pereira S . Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome. PLoS One. 2016; 11(3):e0151635. PMC: 4798246. DOI: 10.1371/journal.pone.0151635. View