Inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human hepatocellular carcinoma
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Hepatocellular carcinoma (HCC) is the most common form ofprimary liver cancer. HCC occurs people with chronic liverdiseases. The purinergic receptor P2X 7 (P2RX7) is involved intumor proliferation and growth. Also, P2RX7 is associated withtumor invasion and metastatic dissemination. High glucose utilizationis important for the survival of various types of tumors. However, the role of P2RX7 in glucose metabolism and cellularsurvival of HCC remains unclear. Here, our results show thatthe gene and protein levels of P2RX7 were elevated in tumor cellsof patients with HCC. The pharmacological inhibition of P2RX7by A-804598, a selective P2RX7 antagonist, and genetic inhibitionby P2RX7 knockdown suppressed the glycolytic activity byreduction of hexokinase 2 (HK2), a key enzyme of the glycolysispathway, in human HCC cells. Also, both A-804598 treatment andP2RX7 knockdown induced cytotoxicity via inhibition of AKTactivation which is critical for tumor cell survival in human HCCcells. Moreover, A-804598 treatment and P2RX7 knockdown increasedcytotoxicity and caspase-3 activation in human HCC cells. Theseresults suggest that inhibition of P2RX7 contributes to cytotoxicityby suppression of glycolysis and AKT activation in human HCC.
Abstract
Hepatocellular carcinoma (HCC) is the most common form ofprimary liver cancer. HCC occurs people with chronic liverdiseases. The purinergic receptor P2X 7 (P2RX7) is involved intumor proliferation and growth. Also, P2RX7 is associated withtumor invasion and metastatic dissemination. High glucose utilizationis important for the survival of various types of tumors. However, the role of P2RX7 in glucose metabolism and cellularsurvival of HCC remains unclear. Here, our results show thatthe gene and protein levels of P2RX7 were elevated in tumor cellsof patients with HCC. The pharmacological inhibition of P2RX7by A-804598, a selective P2RX7 antagonist, and genetic inhibitionby P2RX7 knockdown suppressed the glycolytic activity byreduction of hexokinase 2 (HK2), a key enzyme of the glycolysispathway, in human HCC cells. Also, both A-804598 treatment andP2RX7 knockdown induced cytotoxicity via inhibition of AKTactivation which is critical for tumor cell survival in human HCCcells. Moreover, A-804598 treatment and P2RX7 knockdown increasedcytotoxicity and caspase-3 activation in human HCC cells. Theseresults suggest that inhibition of P2RX7 contributes to cytotoxicityby suppression of glycolysis and AKT activation in human HCC.
참고문헌 (37)
- Collaborators GBDCoD, "Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017 : a systematic analysis for the Global Burden of Disease Study 2017", Lancet, 392, pp.1736~1788 (2018)
- Llovet JM, "Hepatocellular carcinoma : present status and future prospects", J Hepatol, 1, pp.S136~149 (2003)
- Farazi PA, "Hepatocellular carcinoma pathogenesis : from genes to environment", Nat Rev Cancer, 6, pp.674~687 (2006)
- Anstee QM, "From NASH to HCC : current concepts and future challenges", Nat Rev Gastroenterol Hepatol, 16, pp.411~428 (2019)
- Hsu PP, "Cancer cell metabolism : Warburg and beyond", Cell, 134, pp.703~707 (2008)
- Vander Heiden MG, "Understanding the Warburg effect : the metabolic requirements of cell proliferation", Science, 324, pp.1029~1033 (2009)
- Xia H, "Reprogramming of central carbon metabolism in hepatocellular carcinoma", Biomed Pharmacother, 153, pp.113485~ (2022)
- Jang M, "Cancer cell metabolism : implications for therapeutic targets", Exp Mol Med, 45, pp.e45~ (2013)
- Mathupala SP, "Hexokinase-2bound to mitochondria : cancer's stygian link to the Warburg Effect and a pivotal target for effective therapy", Semin Cancer Biol, 19, pp.17~24 (2009)
- Hay N, "Reprogramming glucose metabolism in cancer : can it be exploited for cancer therapy?", Nat Rev Cancer, 16, pp.635~649 (2016)
- Mathupala SP, "Hexokinase II : cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria", Oncogene, 25, pp.4777~4786 (2006)
- Guzman G, "Evidence for heightened hexokinase II immunoexpression in hepatocyte dysplasia and hepatocellular carcinoma", Dig Dis Sci, 60, pp.420~426 (2015)
- Sluyter R, "The P2X7 receptor", Adv Exp Med Biol, 1051, pp.17~53 (2017)
- Collo G, "Tissue distribution of the P2X7receptor", Neuropharmacology, 36, pp.1277~1283 (1997)
- Pelegrin P, "P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophage", J Immunol, 180, pp.7147~7157 (2008)
- Qu Y, "P2X7 receptors regulate multiple types of membrane trafficking responses and nonclassical secretion pathways", Purinergic Signal, 5, pp.163~173 (2009)
- Amoroso F, "The P2X7 receptor is a key modulator of aerobic glycolysis", Cell Death Dis, 3, pp.e370~ (2012)
- Roger S, "Understanding the roles of the P2X7 receptor in solid tumour progression and therapeutic perspectives", Biochim Biophys Acta, 1848, pp.2584~2602 (2015)
- Li X, "Research progress on the P2X7 receptor in liver injury and hepatocellular carcinoma", Chem Biol Drug Des, 101, pp.794~808 (2023)
- Liu H, "Prognostic value of purinergic P2X7 receptor expression in patients with hepatocellular carcinoma after curative resection", Tumour Biol, 36, pp.5039~5049 (2015)
- Asif A, "Role of purinergic receptors in hepatobiliary carcinoma in Pakistani population : an approach towards proinflammatory role of P2X4 and P2X7 receptors", Purinergic Signal, 15, pp.367~374 (2019)
- Matschinsky FM, "Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes", Diabetes, 39, pp.647~652 (1990)
- Guo D, "Hexokinases in cancer and other pathologies", Cell Insight, 2, pp.100077~ (2023)
- Feng J, "Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma", J Exp Clin Cancer Res, 39, pp.126~ (2020)
- Robey RB, "Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt", Oncogene, 25, pp.4683~4696 (2006)
- Ye Y, "Glutamine metabolic reprogramming in hepatocellular carcinoma", Front Mol Biosci, 10, pp.1242059~ (2023)
- Marsico M, "Mitochondria-mediated apoptosis of HCC cells triggered by knockdown of glutamate dehydrogenase 1 : perspective for its inhibition through quercetin and permethylated anigopreissin A", Biomedicines, 9, pp.1664~ (2021)
- Shen A, "A systematic review of sorafenib in Child-Pugh A patients with unresectable hepatocellular carcinoma", J Clin Gastroenterol, 47, pp.871~880 (2013)
- Facciorusso A, "Lenvatinib versus sorafenib as first-line therapy of advanced hepatocellular carcinoma : a systematic review and metaanalysis", Am J Transl Res, 13, pp.2379~2387 (2021)
- Finn RS, "Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma", N Engl J Med, 382, pp.1894~1905 (2020)
- Abou-Alfa GK, "Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma", NEJM Evid 1 (2022)
- Faria RX, "P2X7 receptor large pore signaling in avian Muller glial cells", J Bioenerg Biomembr, 49, pp.215~229 (2017)
- Freitas HR, "Glutathione induces GABA release through P2X(7)R activation on Muller glia", Neurogenesis(Austin), 4, pp.e1283188~ (2017)
- Freitas HR, "Glutathioneinduced calcium shifts in chick retinal glial cells", PLoS One, 11, pp.e0153677~ (2016)
- Kawano A, "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages", Biochem Biophys Res Commun, 419, pp.374~380 (2012)
- Shigemoto-Mogami Y, "Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5", J Neurochem, 78, pp.1339~1349 (2001)
- Kataoka A, "Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT", J Neurochem, 108, pp.115~125 (2009)