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Insulin Resistance Reduces Sensitivity to Cis-Platinum and Promotes Adhesion, Migration and Invasion in HepG2 Cells

  • Li, Lin-Jing (Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University) ;
  • Li, Guang-Di (Department of Clinical Laboratory, the Second Hosiptal of Lanzhou University) ;
  • Wei, Hu-Lai (Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University) ;
  • Chen, Jing (Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University) ;
  • Liu, Yu-Mei (Department of Clinical Laboratory, the Second Hosiptal of Lanzhou University) ;
  • Li, Fei (Department of Clinical Laboratory, the Second Hosiptal of Lanzhou University) ;
  • Xie, Bei (Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University) ;
  • Wang, Bei (Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University) ;
  • Li, Cai-Li (Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University)
  • Published : 2014.04.01

Abstract

The liver is normally the major site of glucose metabolism in intact organisms and the most important target organ for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drug resistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubation with a high concentration of insulin. Once the insulin-resistant cell line was established, the stability of HepG2/IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biological effects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells were determined. The results indicated that glucose consumption was reduced in insulin-resistant cells. In addition, the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IR cells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited a lower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatment with the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drug resistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain the clinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasion and migration of cancer cells.

Keywords

Hepatocellular carcinoma;insulin resistance;proliferation;pioglitazone hydrochloride

References

  1. Yoshikawa T, Noguchi Y, Doi C, Makino T, Nomura K (2001). Insulin resistance in patients with cancer: relationships with tumor site, tumor stage, body-weight loss, acute-phase response, and energy expenditure. Nutrition, 17, 590-3. https://doi.org/10.1016/S0899-9007(01)00561-5
  2. Tsujimoto M, Aozasa K, Nakajima Y, Kariya M (1984). Hepatocellular carcinoma with sarcomatous proliferation showing an unusual and wide-spread metastasis. Acta Pathol Jpn, 34, 839-45.
  3. Turati F, Talamini R, Pelucchi C, et al (2013). Metabolic syndrome and hepatocellular carcinoma risk. Br J Cancer, 108, 222-8. https://doi.org/10.1038/bjc.2012.492
  4. Wilcox G (2005). Insulin and insulin resistance. Clin Biochem Rev, 26, 19-39.
  5. Yao Z, Che XC, Lu R, et al (2007). Inhibition by tyroserleutide (YSL) on the invasion and adhesion of the mouse melanoma cell. Mol Med, 13, 14-21.
  6. Melin B, Cherqui G, Blivet MJ, et al (1990). Dual effect of metformin in cultured rat hepatocytes: potentiation of insulin action and prevention of insulin-induced resistance. Metabolism, 39, 1089-95. https://doi.org/10.1016/0026-0495(90)90171-8
  7. Ledoux S, Yang R, Friedlander G, Laouari D (2003). Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. Cancer Res, 63, 7284-90.
  8. Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A (2007). Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol, 47, 142-56. https://doi.org/10.1016/j.jhep.2007.04.002
  9. Loberg RD, Bradley DA, Tomlins SA, Chinnaiyan AM, Pienta KJ (2007). The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J Clin, 57, 225-41. https://doi.org/10.3322/canjclin.57.4.225
  10. Macaulay SL, Polites M, Frenkel MJ, Hewish DR, Ward CW (1995). Mutagenic structure/function analysis of the cytoplasmic cysteines of the insulin receptor. Biochem J, 306, 811-20. https://doi.org/10.1042/bj3060811
  11. Soliman PT, Wu D, Tortolero-Luna G, et al (2006). Association between adiponectin, insulin resistance, and endometrial cancer. Cancer, 106, 2376-81. https://doi.org/10.1002/cncr.21866
  12. Su JL, Yang PC, Shih JY, et al (2006). The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell, 9, 209-23. https://doi.org/10.1016/j.ccr.2006.02.018
  13. Sawai H, Domae N (2011). Discrimination between primary necrosis and apoptosis by necrostatin-1 in Annexin V-positive/propidium iodide-negative cells. Biochem Biophys Res Commun, 411, 569-73. https://doi.org/10.1016/j.bbrc.2011.06.186
  14. Stockert JC, Blazquez-Castro A, Canete M, Horobin RW, Villanueva A (2012). MTT assay for cell viability: Intracellular localization of the formazan product is in lipid droplets. Acta Histochem, 114, 785-96. https://doi.org/10.1016/j.acthis.2012.01.006
  15. Donadon V, Balbi M, Perciaccante A, Casarin P, Zanette G (2009) Insulin resistance and hyperinsulinemia in patients with chronic liver disease and hepatocellular carcinoma. Clinical Medicine Insights: Endocrinology and Diabetes, 2, 25-33.
  16. Cousin JL, Samson M, Pilch PF, Fehlmann M (1987) Internalization of insulin receptors and HLA antigens in human hepatoma cells. Biochem J, 242, 403-10. https://doi.org/10.1042/bj2420403
  17. Cho N, Momose Y (2008). Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress. Curr Top Med Chem, 8, 1483-507. https://doi.org/10.2174/156802608786413474
  18. Draznin B (2006). Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin. Diabetes, 55, 2392-7. https://doi.org/10.2337/db06-0391
  19. Gupta SP, Mittal A, Sathian B. Jha DK (2013). Elevated serum insulin is an independent risk factor for hepatocellular carcinoma: a case control study from Nepal. Asian Pac J Cancer Prev, 14, 7331-3. https://doi.org/10.7314/APJCP.2013.14.12.7331
  20. Hu, XQ, Yuan P, Luan, RS et al (2013). Calpain-10 SNP43 and SNP19 polymorphisms and colorectal cancer: a matched case-control study. Asian Pac J Cancer Prev, 14, 6673-80. https://doi.org/10.7314/APJCP.2013.14.11.6673
  21. Keku TO, Lund PK, Galanko J, et al (2005) Insulin resistance, apoptosis, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev, 14, 2076-81. https://doi.org/10.1158/1055-9965.EPI-05-0239
  22. Kruk J, Czerniak U (2013). Physical activity and its relation to cancer risk: updating the evidence. Asian Pac J Cancer Prev, 14, 3993-4003. https://doi.org/10.7314/APJCP.2013.14.7.3993
  23. Liotta LA, Stetler-Stevenson WG (1991). Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res, 51, 5054-9.

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