Tumor Biology

, Volume 37, Issue 3, pp 3841–3850 | Cite as

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

  • Bingyu Guo
  • Yu Zhang
  • Qiang Hui
  • Hongyi Wang
  • Kai TaoEmail author
Original Article


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.


Naringin A375 cells c-Src Signaling pathway Metabolism 


Compliance with ethical standards

Conflict of interest



  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2013;63:11–30.CrossRefPubMedGoogle Scholar
  2. 2.
    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.PubMedPubMedCentralGoogle Scholar
  3. 3.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    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.CrossRefPubMedGoogle Scholar
  5. 5.
    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.Google Scholar
  6. 6.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    Dehm SM, Bonham K. Src gene expression in human cancer: the role of transcriptional activation. Biochem Cell Biol. 2004;82:263–74.CrossRefPubMedGoogle Scholar
  9. 9.
    Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000;19:5636–42.CrossRefPubMedGoogle Scholar
  10. 10.
    Kumble S, Omary MB, Cartwright CA, Triadafilopoulos G. Src activation in malignant and premalignant epithelia of Barrett’s esophagus. Gastroenterology. 1997;112:348–56.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    Travis J. Cancer. Gleevec, chapter two: new leukemia drug aims to overcome resistance. Science. 2004;305:319–21.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.PubMedGoogle Scholar
  20. 20.
    Bharti S, Rani N, Krishnamurthy B, Arya DS. Preclinical evidence for the pharmacological actions of naringin: a review. Planta Med. 2014;80:437–51.CrossRefPubMedGoogle Scholar
  21. 21.
    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.Google Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang Y, Yang JM. Altered energy metabolism in cancer: a unique opportunity for therapeutic intervention. Cancer BiolTher. 2013;14:81–9.Google Scholar
  27. 27.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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.PubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    Yeatman TJ. A renaissance for Src. Nat Rev Cancer. 2004;4:470–80.CrossRefPubMedGoogle Scholar
  36. 36.
    Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003;22:337–58.CrossRefPubMedGoogle Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    Frame MC. Newest findings on the oldest oncogene; how activated Src does it. J Cell Sci. 2004;117:989–98.CrossRefPubMedGoogle Scholar
  39. 39.
    Parsons SJ, Parsons JT. Src family kinases, key regulators of signal transduction. Oncogene. 2004;23:7906–9.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Bingyu Guo
    • 1
  • Yu Zhang
    • 1
  • Qiang Hui
    • 1
  • Hongyi Wang
    • 1
  • Kai Tao
    • 1
    Email author
  1. 1.Reconstructive and Plastic SurgeryThe General Hospital of Shenyang Military RegionShenyangChina

Personalised recommendations