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 andincreased 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 inc rease in the expression and activation of the IGF-IR was observed during th e transition of growth states from exponential to quiescent. The increase i n IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript an d is associated with an increase in the IGF-IR promoter activity. Inhibitio n of de novo transcription by actinomycin D increased the stability of IGF- IR mRNA in exponentially growing cells, thereby increasing the expression o f 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 ki nase (MAPK). Exogenous IGF-I increased cell proliferation and activated MAP K and AKT signaling pathways. The resistance of cells to apoptosis by IGF-I R signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI 3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation o f IGF-1R signaling is required for resistance to apoptosis and growth facto r independence of MIA PaCa-2 cells. This likely protects cells from unfavor able conditions and allows cells to rapidly re-enter the cell cycle when co nditions are favorable.