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DOI QR Code

EGF Reverses Multi-drug Resistance via the p-ERK Pathway in HepG2/ADM and SMMC7721/ADM Hepatocellular Carcinoma Models

  • Yan, Feng ;
  • Bai, Li-Ping ;
  • Gao, Hua ;
  • Zhu, Chang-Ming ;
  • Lin, Li ;
  • Kang, Xiang-Peng
  • Published : 2014.03.30

Abstract

Aim: To investigate signaling pathways for reversal of EGF-mediated multi-drug resistance (MDR) in hepatocellular carcinoma (HCC) models. Materials and Methods: HCC MDR cell strain HepG2/adriamycin (ADM) and SMMC7721/ADM models were established using a method of exposure to medium with ADM between low and high concentration with gradually increasing concentration. Drug sensitivity and reversal of multi-drug resistance by EGF were determined and the cell cycle distribution and apoptosis were analyzed by flow cytometry. Phosphorylation of ERK1, ERK2, ERK5 and expression of Bim were detected by Western blotting. Results: The results showed that HepG2/ADM and SMMC7721/ADM cells were resistant not only to ADM, but also to multiple anticancer drugs. When used alone, EGF had no anti-tumor activity in HepG2/ADM and SMMC7721/ADM cells in vitro, while it increased the cytotoxicity of ADM. EGF induced cell apoptosis and G0/G1 phase cell cycle arrest in HepG2/ADM And SMMC7721/ADM cells, while enhancing activity of p-ERKs and up-regulated expression of BimEL. Conclusions: EGF might enhance the chemosensitivity of HepG2/ADM and SMMC7721/ADM cells via up-regulating p-ERKs and BimEL protein.

Keywords

Hepatocellular carcinoma;multi-drug resistance;EGF;ERK;BimEL

References

  1. Ren YQ, Han JQ, Cao JB, et al (2012). Association of MDR1 gene polymorphisms with susceptibility to hepatocellular carcinoma in the Chinese population. Asian Pac J Cancer Prev, 13, 5451-4. https://doi.org/10.7314/APJCP.2012.13.11.5451
  2. Nishimoto S and Nishida E (2006). MAPK signalling: ERK5 versus ERK1/2. EMBO reports, 8, 782-6.
  3. Ozdemir S, Uludag A, Silan F, et al (2013). Possible roles of the xenobiotic transporter P-glycoproteins encoded by the MDR1 3435 C>T gene polymorphism in differentiated thyroid cancers. Asian Pac J Cancer Prev, 14, 3213-7. https://doi.org/10.7314/APJCP.2013.14.5.3213
  4. Perez-Tomas R (2006). Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem, 13, 1859-76. https://doi.org/10.2174/092986706777585077
  5. Roy M and Mukherjee S (2014). Reversal of resistance towards cisplatin by curcumin in cervical cancer cells. Asian Pac J Cancer Prev, 15, 1403-10. https://doi.org/10.7314/APJCP.2014.15.3.1403
  6. Wakamatsu T, Nakahashi Y, Hachimine D, et al (2007). The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance-associated proteins. Int J Oncol, 31, 1465-72.
  7. Yan F, Jiang Y, Li YM, et al (2008). Reversal of P-glycoprotein and multidrug resistance-associated protein 1 mediated multidrug resistance in cancer cells by HZ08 Isomers, tetrataisohydroquinolin derivatives. Biol Pharm Bull, 31, 1258-64. https://doi.org/10.1248/bpb.31.1258
  8. Yan F, Wang XM, Pan C, et al (2009). Down-regulation of extracellular signal-regulated kinase 1/2 activity in P-glycoprotein-mediated multidrug resistant hepatocellular carcinoma cells. World J Gastroenterol, 15, 1443-51. https://doi.org/10.3748/wjg.15.1443
  9. Zhu CY1, Lv YP, Yan DF, et al (2013). Knockdown of MDR1 increases the sensitivity to adriamycin in drug resistant gastric cancer cells. Asian Pac J Cancer Prev. 14, 6757-60. https://doi.org/10.7314/APJCP.2013.14.11.6757
  10. Chen SY, Hu SS, Dong Q, et al (2013). Establishment of paclitaxel-resistant breast cancer cell line and nude mice models, and underlying multidrug resistance mechanisms in vitro and in vivo. Asian Pac J Cancer Prev, 14, 6135-40. https://doi.org/10.7314/APJCP.2013.14.10.6135
  11. Avruch J (2007). MAP kinase pathways: the first twenty years. Biochim Biophys Acta, 1773, 1150-60. https://doi.org/10.1016/j.bbamcr.2006.11.006
  12. Bustamante J Picard C, Fieschi C (2007). A novel X-linked recessive form of Mendelian susceptibility to mycobaterial disease. J Med Genet, 44, 65.
  13. Chen B, Sun Q, Wang X, et al (2008). Reversal in multidrug resistance by magnetic nanoparticle of $Fe_{3}O_{4}$ oaded with adriamycin and tetrandrine in K562/A02 leukemic cells. Int J Nanomed, 3, 277-286.
  14. Chow KC, Tang CN, Lai ECh, et al (2013). Curative treatment for recurrent tumour implantation after ruptured hepatocellular carcinoma. Hong Kong Med J, 19, 82-84.
  15. Chen SF, Nieh S, Jao SW, et al (2012). Quercetin Suppresses Drug-Resistant Spheres via the p38 MAPK-Hsp27 Apoptotic Pathway in Oral Cancer Cells. PLOS ONE, 7, 111-9.
  16. Claessens YE, Bouscary D, Dupont JM, et al (2002). In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent apoptosis. Blood, 99, 1594-601. https://doi.org/10.1182/blood.V99.5.1594
  17. Fang JY and Richardson BC (2005). The MAPK signalling pathways and colorectal cancer. Lancet Oncol, 6, 322-7. https://doi.org/10.1016/S1470-2045(05)70168-6
  18. Korhonen L, Belluardo N, Mudo G, Lindholm D (2003). Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain. Eur J Neurosci, 18, 1121-34. https://doi.org/10.1046/j.1460-9568.2003.02826.x
  19. Li Y, Li S, Han Y, et al (2008). Calebin-A induces apoptosis and modulates MAPK family activity in drug resistant human gastric cancer cells. Eur J Pharmacol, 591, 252-8. https://doi.org/10.1016/j.ejphar.2008.06.065

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