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Erschienen in: Tumor Biology 3/2016

17.10.2015 | Original Article

Naringin suppresses the metabolism of A375 cells by inhibiting the phosphorylation of c-Src

Erschienen in: Tumor Biology | Ausgabe 3/2016

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Abstract

Elevation of glycolysis, increase in lactic acid production, and enhancement of mitochondrial biogenesis are all the changes of energy metabolism of melanoma cells. Melanoma cells’ metabolism and energy production networks play an important role in cancer proliferation, survival, motility, invasiveness, metastasis, and angiogenesis. Since the Warburg theory was put forward in the 1930s, more researchers focus on finding new ways for effectively eliminating cancer cells by targeting their energy metabolism. In this study, we found naringin has the inhibitory effects on the glucose metabolism of A375 cells, a melanoma cell line, in a concentration-dependent manner. We also found that naringin could significantly reduce the phosphorylation of c-Src. In summary, we demonstrated that naringin inhibits the malignant phenotype of A375 cells by suppressing c-Src and its downstream signaling pathway. More importantly, we provide the novel mechanism that, as a natural inhibitor of c-Src, naringin could be an effective candidate for the treatment of melanoma.
Literatur
1.
2.
Zurück zum Zitat Grazia G, Penna I, Perotti V, Anichini A, Tassi E. Towards combinatorial targeted therapy in melanoma: from pre-clinical evidence to clinical application (review). Int J Oncol. 2014;45:929–49.PubMedPubMedCentral Grazia G, Penna I, Perotti V, Anichini A, Tassi E. Towards combinatorial targeted therapy in melanoma: from pre-clinical evidence to clinical application (review). Int J Oncol. 2014;45:929–49.PubMedPubMedCentral
3.
Zurück zum Zitat Ascierto PA, Grimaldi AM, Acquavella N, Borgognoni L, Calabro L, Cascinelli N, et al. Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd–4th 2012”. J Transl Med. 2013;11:137.CrossRefPubMedPubMedCentral Ascierto PA, Grimaldi AM, Acquavella N, Borgognoni L, Calabro L, Cascinelli N, et al. Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd–4th 2012”. J Transl Med. 2013;11:137.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Lee JH, Pyon JK, Kim DW, Lee SH, Nam HS, Kim CH, et al. Elevated c-Src and c-Yes expression in malignant skin cancers. J Exp ClinCancer Res CR. 2010;29:116.CrossRefPubMed Lee JH, Pyon JK, Kim DW, Lee SH, Nam HS, Kim CH, et al. Elevated c-Src and c-Yes expression in malignant skin cancers. J Exp ClinCancer Res CR. 2010;29:116.CrossRefPubMed
5.
Zurück zum Zitat O'Connor TJ, Neufeld E, Bechberger J, Fujita DJ. pp60c-src in human melanocytes and melanoma cells exhibits elevated specific activity and reduced tyrosine 530 phosphorylation compared to human fibroblast pp60c-src. Cell Growth Differ: Mol Biol J American Assoc Cancer Res. 1992;3:435–42. O'Connor TJ, Neufeld E, Bechberger J, Fujita DJ. pp60c-src in human melanocytes and melanoma cells exhibits elevated specific activity and reduced tyrosine 530 phosphorylation compared to human fibroblast pp60c-src. Cell Growth Differ: Mol Biol J American Assoc Cancer Res. 1992;3:435–42.
6.
Zurück zum Zitat Lu KV, Zhu S, Cvrljevic A, Huang TT, Sarkaria S, Ahkavan D, et al. Fyn and SRC are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients. Cancer Res. 2009;69:6889–98.CrossRefPubMedPubMedCentral Lu KV, Zhu S, Cvrljevic A, Huang TT, Sarkaria S, Ahkavan D, et al. Fyn and SRC are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients. Cancer Res. 2009;69:6889–98.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, et al. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11:7234–42.CrossRef Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, et al. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11:7234–42.CrossRef
8.
Zurück zum Zitat Dehm SM, Bonham K. Src gene expression in human cancer: the role of transcriptional activation. Biochem Cell Biol. 2004;82:263–74.CrossRefPubMed Dehm SM, Bonham K. Src gene expression in human cancer: the role of transcriptional activation. Biochem Cell Biol. 2004;82:263–74.CrossRefPubMed
9.
Zurück zum Zitat Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000;19:5636–42.CrossRefPubMed Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000;19:5636–42.CrossRefPubMed
10.
Zurück zum Zitat Kumble S, Omary MB, Cartwright CA, Triadafilopoulos G. Src activation in malignant and premalignant epithelia of Barrett’s esophagus. Gastroenterology. 1997;112:348–56.CrossRefPubMed Kumble S, Omary MB, Cartwright CA, Triadafilopoulos G. Src activation in malignant and premalignant epithelia of Barrett’s esophagus. Gastroenterology. 1997;112:348–56.CrossRefPubMed
11.
Zurück zum Zitat Sun V, Zhou WB, Nosrati M, Majid S, Thummala S, de Semir D, et al. Antitumor activity of miR-1280 in melanoma by regulation of Src. Mol Ther: J Am Society Gene Ther. 2015;23:71–8.CrossRef Sun V, Zhou WB, Nosrati M, Majid S, Thummala S, de Semir D, et al. Antitumor activity of miR-1280 in melanoma by regulation of Src. Mol Ther: J Am Society Gene Ther. 2015;23:71–8.CrossRef
12.
Zurück zum Zitat Lodeiro M, Theodoropoulou M, Pardo M, Casanueva FF, Camina JP. c-Src regulates Akt signaling in response to ghrelin via beta-arrestin signaling-independent and -dependent mechanisms. PLoS One. 2009;4:e4686.CrossRefPubMedPubMedCentral Lodeiro M, Theodoropoulou M, Pardo M, Casanueva FF, Camina JP. c-Src regulates Akt signaling in response to ghrelin via beta-arrestin signaling-independent and -dependent mechanisms. PLoS One. 2009;4:e4686.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Warmuth M, Damoiseaux R, Liu Y, Fabbro D, Gray N. Src family kinases: potential targets for the treatment of human cancer and leukemia. Curr Pharm Des. 2003;9:2043–59.CrossRefPubMed Warmuth M, Damoiseaux R, Liu Y, Fabbro D, Gray N. Src family kinases: potential targets for the treatment of human cancer and leukemia. Curr Pharm Des. 2003;9:2043–59.CrossRefPubMed
14.
Zurück zum Zitat Choudhury GG, Mahimainathan L, Das F, Venkatesan B, Ghosh-Choudhury N. C-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells. Cell Signal. 2006;18:1854–64.CrossRefPubMed Choudhury GG, Mahimainathan L, Das F, Venkatesan B, Ghosh-Choudhury N. C-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells. Cell Signal. 2006;18:1854–64.CrossRefPubMed
15.
Zurück zum Zitat Buettner R, Mesa T, Vultur A, Lee F, Jove R. Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res: MCR. 2008;6:1766–74.CrossRefPubMedPubMedCentral Buettner R, Mesa T, Vultur A, Lee F, Jove R. Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res: MCR. 2008;6:1766–74.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. Discovery of n-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61.CrossRefPubMed Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. Discovery of n-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61.CrossRefPubMed
17.
Zurück zum Zitat Travis J. Cancer. Gleevec, chapter two: new leukemia drug aims to overcome resistance. Science. 2004;305:319–21.CrossRefPubMed Travis J. Cancer. Gleevec, chapter two: new leukemia drug aims to overcome resistance. Science. 2004;305:319–21.CrossRefPubMed
18.
Zurück zum Zitat Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel Abl kinase inhibitor. Science. 2004;305:399–401.CrossRefPubMed Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel Abl kinase inhibitor. Science. 2004;305:399–401.CrossRefPubMed
19.
Zurück zum Zitat Raha S, Yumnam S, Hong GE, Lee HJ, Saralamma VV, Park HS, et al. Naringin induces autophagy-mediated growth inhibition by downregulating the PI3k/Akt/mTOR cascade via activation of MAPK pathways in AGS cancer cells. Int J Oncol. 2015;47:1061–9.PubMed Raha S, Yumnam S, Hong GE, Lee HJ, Saralamma VV, Park HS, et al. Naringin induces autophagy-mediated growth inhibition by downregulating the PI3k/Akt/mTOR cascade via activation of MAPK pathways in AGS cancer cells. Int J Oncol. 2015;47:1061–9.PubMed
20.
Zurück zum Zitat Bharti S, Rani N, Krishnamurthy B, Arya DS. Preclinical evidence for the pharmacological actions of naringin: a review. Planta Med. 2014;80:437–51.CrossRefPubMed Bharti S, Rani N, Krishnamurthy B, Arya DS. Preclinical evidence for the pharmacological actions of naringin: a review. Planta Med. 2014;80:437–51.CrossRefPubMed
21.
Zurück zum Zitat Banjerdpongchai R, Wudtiwai B, Khaw-On P, Rachakhom W, Duangnil N, Kongtawelert P. Hesperidin from citrus seed induces human hepatocellular carcinoma hepg2 cell apoptosis via both mitochondrial and death receptor pathways. Tumour Biol: J Int Soc Oncodev Biol Med 2015. Banjerdpongchai R, Wudtiwai B, Khaw-On P, Rachakhom W, Duangnil N, Kongtawelert P. Hesperidin from citrus seed induces human hepatocellular carcinoma hepg2 cell apoptosis via both mitochondrial and death receptor pathways. Tumour Biol: J Int Soc Oncodev Biol Med 2015.
22.
Zurück zum Zitat Takumi S, Ikema S, Hanyu T, Shima Y, Kurimoto T, Shiozaki K, et al. Naringin attenuates the cytotoxicity of hepatotoxin microcystin-LR by the curious mechanisms to OATP1B1- and OATP1B3-expressing cells. Environ Toxicol Pharmacol. 2015;39:974–81.CrossRefPubMed Takumi S, Ikema S, Hanyu T, Shima Y, Kurimoto T, Shiozaki K, et al. Naringin attenuates the cytotoxicity of hepatotoxin microcystin-LR by the curious mechanisms to OATP1B1- and OATP1B3-expressing cells. Environ Toxicol Pharmacol. 2015;39:974–81.CrossRefPubMed
23.
Zurück zum Zitat Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentral Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Iqbal MA, Bamezai RN. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS One. 2012;7:e36764.CrossRefPubMedPubMedCentral Iqbal MA, Bamezai RN. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS One. 2012;7:e36764.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.CrossRefPubMed Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.CrossRefPubMed
26.
Zurück zum Zitat Zhang Y, Yang JM. Altered energy metabolism in cancer: a unique opportunity for therapeutic intervention. Cancer BiolTher. 2013;14:81–9. Zhang Y, Yang JM. Altered energy metabolism in cancer: a unique opportunity for therapeutic intervention. Cancer BiolTher. 2013;14:81–9.
27.
Zurück zum Zitat Bluemlein K, Gruning NM, Feichtinger RG, Lehrach H, Kofler B, Ralser M. No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis. Oncotarget. 2011;2:393–400.CrossRefPubMedPubMedCentral Bluemlein K, Gruning NM, Feichtinger RG, Lehrach H, Kofler B, Ralser M. No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis. Oncotarget. 2011;2:393–400.CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–21.PubMed Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–21.PubMed
29.
Zurück zum Zitat Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.CrossRefPubMed Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.CrossRefPubMed
30.
Zurück zum Zitat Vadde R, Radhakrishnan S, Reddivari L, Vanamala JK. Triphala extract suppresses proliferation and induces apoptosis in human colon cancer stem cells via suppressing c-Myc/Cyclin D1 and elevation of Bax/Bcl-2 ratio. BioMed Res Int. 2015;2015:649263.CrossRefPubMedPubMedCentral Vadde R, Radhakrishnan S, Reddivari L, Vanamala JK. Triphala extract suppresses proliferation and induces apoptosis in human colon cancer stem cells via suppressing c-Myc/Cyclin D1 and elevation of Bax/Bcl-2 ratio. BioMed Res Int. 2015;2015:649263.CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Li H, Yang B, Huang J, Xiang T, Yin X, Wan J, et al. Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting beta-catenin signaling pathway. Toxicol Lett. 2013;220:219–28.CrossRefPubMed Li H, Yang B, Huang J, Xiang T, Yin X, Wan J, et al. Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting beta-catenin signaling pathway. Toxicol Lett. 2013;220:219–28.CrossRefPubMed
32.
Zurück zum Zitat Chen Y, Nie YC, Luo YL, Lin F, Zheng YF, Cheng GH, et al. Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. Food Chem Toxicol: Int J Publ Br Ind Biol Res Assoc. 2013;58:133–40.CrossRef Chen Y, Nie YC, Luo YL, Lin F, Zheng YF, Cheng GH, et al. Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. Food Chem Toxicol: Int J Publ Br Ind Biol Res Assoc. 2013;58:133–40.CrossRef
33.
Zurück zum Zitat Homsi J, Cubitt C, Daud A. The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets. 2007;11:91–100.CrossRefPubMed Homsi J, Cubitt C, Daud A. The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets. 2007;11:91–100.CrossRefPubMed
34.
Zurück zum Zitat Masaki T, Igarashi K, Tokuda M, Yukimasa S, Han F, Jin YJ, et al. pp60c-Src activation in lung adenocarcinoma. Eur J Cancer. 2003;39:1447–55.CrossRefPubMed Masaki T, Igarashi K, Tokuda M, Yukimasa S, Han F, Jin YJ, et al. pp60c-Src activation in lung adenocarcinoma. Eur J Cancer. 2003;39:1447–55.CrossRefPubMed
36.
Zurück zum Zitat Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003;22:337–58.CrossRefPubMed Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003;22:337–58.CrossRefPubMed
37.
Zurück zum Zitat Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 2005;65:9185–9.CrossRefPubMed Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 2005;65:9185–9.CrossRefPubMed
38.
Zurück zum Zitat Frame MC. Newest findings on the oldest oncogene; how activated Src does it. J Cell Sci. 2004;117:989–98.CrossRefPubMed Frame MC. Newest findings on the oldest oncogene; how activated Src does it. J Cell Sci. 2004;117:989–98.CrossRefPubMed
39.
Zurück zum Zitat Parsons SJ, Parsons JT. Src family kinases, key regulators of signal transduction. Oncogene. 2004;23:7906–9.CrossRefPubMed Parsons SJ, Parsons JT. Src family kinases, key regulators of signal transduction. Oncogene. 2004;23:7906–9.CrossRefPubMed
40.
Zurück zum Zitat Gianni D, Bohl B, Courtneidge SA, Bokoch GM. The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1. Mol Biol Cell. 2008;19:2984–94.CrossRefPubMedPubMedCentral Gianni D, Bohl B, Courtneidge SA, Bokoch GM. The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1. Mol Biol Cell. 2008;19:2984–94.CrossRefPubMedPubMedCentral
Metadaten
Titel
Naringin suppresses the metabolism of A375 cells by inhibiting the phosphorylation of c-Src
Publikationsdatum
17.10.2015
Erschienen in
Tumor Biology / Ausgabe 3/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4235-z

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