Role and Activation Status of IRS1/2 in IL-4-induced Protection from Cell Death.

Porter, Holly

Abstract

IL-4 is a cytokine with many functions that is produced mainly by TH2 cells, basophils, and mast cells, but is also expressed by NK T cells, gamma/delta T cells, and eosinophils. There are two main signaling pathways activated by IL-4;the STAT6, signal transducers and activators of transcription, pathway that results in expression of IL-4-responsive genes and the IRS1/2 signaling pathway that influences cellular proliferation and survival. Having a decreased Th1/Th2 ratio is observed in many cancers and although this impairs cytotoxity against tumors, cytokines such as IL-4 do not act simply by modulating the immune response. IL-4 can also act directly on many tumor cell types to prevent apoptosis. Both the STAT6 pathway and the IRS1/IRS2 proteins have been associated with cancer due to their impact on regulation of anti-apoptotic proteins and control of cell proliferation. Most studies have focused solely on the contribution of the STAT6 pathway and its ability to upregulate Bcl-xL. Fewer studies have examined the role and activation status of IRS1 or IRS2 in IL-4-induced protection from cell-death. Based on the published findings and our preliminary data, we propose that IRS1 and IRS2 differentially contribute to the responsiveness of cells to chemotherapy. We have found that expression of IRS1 leads to enhanced sensitivity to chemotherapy-induced cell death in 32D cells. We hypothesize that these effects are mediated through the differential phosphorylation of IRS1 and IRS2, and the activation or inactivation of downstream regulators of the cell cycle (i.e. c-myc, p27, cyclins, and CDKs) and apoptosis (i.e. Bcl- xL, cFlipL, pAkt).
Two specific aims are designed to test this hypothesis.
Aim 1 is to define the role of IRS1 and IRS2 in sensitivity to chemotherapy in the model 32D cell system.
Aim 2 is to analyze the role of IRS1 and IRS2 in breast cancer cell resistance to chemotherapy-induced cell death. The ability to antagonize enhanced STAT6 and/or IRS1/2 activation may provide therapeutic targets to efficiently inhibit cancer progression. Understanding the molecular programming of a cell may also allow for the better prediction of a patient's response to treatment.

Public Health Relevance

The ability to antagonize enhanced STAT6 and/or IRS1/2 activation may provide therapeutic targets to efficiently inhibit cancer progression and to enhance the efficacy of chemotherapy in vivo. Understanding the molecular programming of a cell may also allow for the better prediction of a patient's response to treatment.