Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-IR) are mediated by an induction of IGF-IR promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2

In the present study we investigated the mechanisms responsible for and the biological consequences of the constitutive activation of the insulin-like growth factor-1 receptor (IGF-IR) in the MIA PaCa-2 cells. An aberrant increase in the expression and activation of the IGF-IR was observed during the transition of growth states from exponential to quiescent. The increase in IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript and is associated with an increase in the IGF-IR promoter activity. Inhibition of de novo transcription by actinomycin D increased the stability of IGF-IR mRNA in exponentially growing cells, thereby increasing the expression of IGF-IR to a level similar to that seen in quiescent cells. Increased IGF-IR signaling mediated the growth factor independence of quiescent MIA PaCa-2 cells through the constitutive activation of mitogen-activated protein kinase (MAPK). Exogenous IGF-I increased cell proliferation and activated MAPK and AKT signaling pathways. The resistance of cells to apoptosis by IGF-IR signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation of IGF-1R signaling is required for resistance to apoptosis and growth factor independence of MIA PaCa-2 cells. This likely protects cells from unfavorable conditions and allows cells to rapidly re-enter the cell cycle when conditions are favorable.