Abstract
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.
Key words
insulin resistance - insulin receptor - insulin receptor substrate - colon cancer
- chemo-resistance
