Chronic insulin exposure does not cause insulin resistance but is associated with chemo-resistance in colon cancer cells.
Insulin resistance is an adaptive process in insulin-sensitive tissues characterised by reduced insulin receptor (IR) and insulin-receptor substrate (IRS)-1 expression, increased IRS-1 serine phosphorylation and attenuated downstream signalling. We tested whether this molecular phenotype prevails in cancer cells after long-term exposure to insulin. We characterised expression of IR-related molecules, IRS-1 phosphorylation and downstream signalling in a panel of 5 colon cancer cell lines at different insulin exposures: 15 min (100 nM), approximating to acute stimulation; 48 h (100 nM), used to demonstrate adaptive changes; and 12 weeks (20 nM; chronic insulin exposure, CIE), approximating to chronic hyperinsulinaemia. To assess clinical relevance, we determined IC50 values (increased indicating chemo-resistance) in the CIE-treated cells using oxaliplatin, SN38 (irinotecan) and 5-fluorouracil (5-FU). All colon cancer cell lines (HCT 116, HT-29, C32, CaCo2, LoVo) were sensitive to 15 min insulin exposure with increased phosphorylation of Akt, PRAS40 and p70-S6K. At 48 h, there was incomplete or absent features of insulin resistance. In CIE-treated cells, there was reduced IR expression, incomplete IRS-1 adaptation, lack of signalling pathway attenuation and contra-adaptive increases in IRS-1 tyrosine phosphorylation in several cell types. In CIE cells, there were multiple examples of increased IC50 values (2- to 100-fold) following 24-h treatment with oxaliplatin and SN38, but not with 5-FU. We concluded that CIE in colon cancer cells does not completely induce an insulin resistance molecular phenotype but is associated with chemo-resistance. Adaptive changes seen in insulin-sensitive non-neoplastic cells in response to long-term insulin may not extrapolate to neoplastic cells.
Clinical and Experimental Pharmacology (CEP) Group, Paterson Institute for Cancer Research, Manchester, UK.
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I
Baricevic
Clinical and Experimental Pharmacology (CEP) Group, Paterson Institute for Cancer Research, Manchester, UK.
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DL
Roberts
Clinical and Experimental Pharmacology (CEP) Group, Paterson Institute for Cancer Research, Manchester, UK.
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AG
Renehan
D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000503:physiopathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000008:administration & dosage*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D009154:Mutation; D009360:Neoplastic Cells, Circulating; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000032:analysis; D011972:Receptor, Insulin / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt