A PI3K/AKT scaffolding protein, IQ motif–containing GTPase associating protein 1 (IQGAP1), promotes head and neck carcinogenesis

Abstract

Purpose: Head and neck cancer (HNC) is the sixth most common cancer worldwide with a 5-year survival rate of less than 50%. The PI3K/AKT/mTOR signaling pathway is frequently implicated in HNC. Recently, IQ motif–containing GTPase-activating protein 1 (IQGAP1) was discovered to scaffold the PI3K/AKT signaling pathway. IQGAP1 gene expression is increased in HNC, raising the hypothesis that IQGAP1 contributes to HNC. Experimental Design: We performed a combination of in vitro studies using human cancer cell lines treated with a cell-permeable peptide that interferes with IQGAP1's ability to bind to PI3K, and in vivo studies utilizing mice genetically knocked out for the Iqgap1 (Iqgap1–/–). In vivo EGF stimulation assays were used to evaluate PI3K signaling. To study the role of IQGAP1 in HNC, we used a well-validated mouse model that drives HNC via a synthetic oral carcinogen, 4-nitroquinoline 1-oxide (4NQO). Results: IQGAP1 is necessary for efficient PI3K signaling in vitro and in vivo. Disruption of IQGAP1-scaffolded PI3K/AKT signaling reduced HNC cell survival. Iqgap1–/– mice had significantly lower cancer incidences, lesser disease severity, and fewer cancer foci. IQGAP1 protein levels were increased in HNC arising in Iqgap1+/+ mice. The level of PI3K signaling in 4NQO-induced HNC arising in Iqgap1–/– mice was significantly reduced, consistent with the hypothesis that IQGAP1 contributes to HNC at least partly through PI3K signaling. High IQGAP1 expression correlated with reduced survival, and high pS6 levels correlated with high IQGAP1 levels in patients with HNC. Conclusions: These data demonstrate that IQGAP1 contributes to head and neck carcinogenesis.