Abstract B59: A novel mechanism in tumor development and progression

Cancer is a progressive disease that can culminate in acquisition of metastatic potential by tumor cells and directly contributes to patient mortality. An understanding of the involved genetic elements and their cellular networks offer an exceptional opportunity for defining potentially relevant and effective targets for improving cancer therapy. IQGAP1 is a widely conserved effector of CDC42 GTPase and has emerged as a potential oncogene associated with diverse human cancers, however, its role in tumor development and progression remains unclear. Here we discuss a novel mechanism by which IQGAP1 generates neoplastic lesions and promotes progression to metastasis.

Our work shows that IQGAP1 binds mTOR and regulates cell homeostasis. Expression of the N-terminal domain, which binds mTOR, enhances insulin secretion, enlarges the cell size and arrests cytokinesis whereas expression of the C-terminal domain that binds and activates CDC42GTPase, accelerates the cell cycle and decreases the cell size. Expression of full-length or the C-terminal domain also increases serine phosphorylation of IQGAP1 and generates transformed phenotypes that are sensitive to rapamycin and PI3K-Akt1 inhibitors.

These findings suggested that IQGAP1 serves as a phosphorylation-sensitive conformational switch to modulate cell proliferation. Indeed, treatment with EGF increases IQGAP1 phosphorylation and the phosphomimetic, but not the phosphodefective, mutant generates transformed phenotypes and promotes cell invasion. In response to EGF, IQGAP1 attenuates mTORC1 signaling and activates Akt1, which may provide an in vivo mechanism by which it generates neoplastic transformation and progression to metastasis. Thus our work has uncovered a novel pathway CDC42-IQGAP1 -mTORC1 -Akt1 in tumor development and progression that may yield new approaches for cancer detection and treatment.

Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B59.