Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer

Signal transduction pathways and crosstalk activated by insulin/IGF-1 receptor and GPCR systems. The binding of an agonist to its cognate GPCR induces Gq/PLC activation, hydrolysis of PIP₂, generation of Ins(1,4,5)P₃, and Ca²⁺ mobilization as described in the text. DAG, the other product of PLC, activates novel PKCs (δ, ε, θ, η,) and, in synergy with Ca²⁺, conventional PKCs (α, β1, β2, γ). PKD (PKD1, PKD2, and PKD3) operate downstream of DAG and PKCs and lead via inactivation of the Ras/Raf inhibitor RIN1 to ERK pathway activation, potentiating signaling via mutated KRAS. Pathways activated by a typical Gq-coupled receptor are shown in blue. For the sake of clarity, stimulation of mTORC1 by ERK is not indicated in the scheme but is discussed in the text. Insulin/IGF induces PI3-kinase/Akt/TSC/Rheb/mTORC1 pathway, indicated in green. Positive crosstalk to GPCR-induced Ca²⁺ signaling is indicated by the black broken line. A plausible target are regulators of G proteins (RGS), which accelerate G protein inactivation by enhancing their GTPase activity. Negative feedback from S6K and mTORC1 on IRS is also indicated (black solid line). Metformin (chemical structure in the insert) is shown to activate AMPK (broken line) because it does not interact directly with AMPK but increases the level of 5′ AMP in the cell. AMPK opposes mTORC1 by phophorylating TSC2 and raptor, as indicated. AMPK also phosphorylates IRS (on Ser⁷⁸⁹), thereby moderating its activation when the negative feedback is removed by mTORC1 inhibition. See text for further details. Another phase I trial will examine side effects and best dose of metformin when given together with temsirolimus in treating patients with metastatic or unresectable solid tumor or lymphoma.