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

Abstract

Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis, and proliferation. Crosstalk between these signaling systems depends on mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast, and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration.

Figure 1

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 white 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 (white solid line). Metformin (chemical structure in the insert) is shown to activate AMPK with broken lines, 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.