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 GTPaseactivating 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 À/À ). 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 À/À mice had significantly lower cancer incidences, lesser disease severity, and fewer cancer foci. IQGAP1 protein levels were increased in HNC arising in Iqgap1 þ/þ mice. The level of PI3K signaling in 4NQO-induced HNC arising in Iqgap1 À/À 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.

A highway to carcinogenesis: the role of IQGAP1, a signaling scaffolding protein, in head and neck cancer development

“…IQGAP1 is overexpressed in many human cancers, including breast, lung, colorectal cancers and HNSCCs [ 13 , 16 - 18 ]. In HNSCCs, high levels of IQGAP1 expression correlates with poorer prognosis for the patients [ 18 , 19 ]. IQGAP1 binds directly to EGFR and facilitates its ligand-dependent activation [ 20 ].…”

“…In a previous study, IQ3 peptide, a cell permeable peptide containing the PI3K binding motif on IQGAP1, was designed to specifically block the interaction between IQGAP1 and PI3K, and therefore inhibits IQGAP1-mediated PI3K signaling [ 21 ]. Treatment of HNSCC cell lines with IQ3 peptide, suppressed PI3K signaling, and inhibited cell survival, proliferation, migration and invasion, indicating that IQGAP1-mediated PI3K signaling is critical for human HNSCC cells [ 19 , 22 ]. Reducing levels of IQGAP1 also resulted in decreased levels of phosphorylated-AKT (pAKT) in human HNSCC cell lines [ 19 ].…”

“…Treatment of HNSCC cell lines with IQ3 peptide, suppressed PI3K signaling, and inhibited cell survival, proliferation, migration and invasion, indicating that IQGAP1-mediated PI3K signaling is critical for human HNSCC cells [ 19 , 22 ]. Reducing levels of IQGAP1 also resulted in decreased levels of phosphorylated-AKT (pAKT) in human HNSCC cell lines [ 19 ]. Likewise we found that mice germ-line deficient for IQGAP1 ( Iqgap1 -/- , [ 23 ]) showed reduced levels of both pAKT and phosphorylated-S6 (pS6, downstream of AKT), compared to wild type ( Iqgap1 +/+ ) mice, when stimulated with EGF [ 19 ], demonstrating that IQGAP1 contributes to the efficiency of the EGFR/PI3K signaling pathway in vivo .…”

“…Reducing levels of IQGAP1 also resulted in decreased levels of phosphorylated-AKT (pAKT) in human HNSCC cell lines [ 19 ]. Likewise we found that mice germ-line deficient for IQGAP1 ( Iqgap1 -/- , [ 23 ]) showed reduced levels of both pAKT and phosphorylated-S6 (pS6, downstream of AKT), compared to wild type ( Iqgap1 +/+ ) mice, when stimulated with EGF [ 19 ], demonstrating that IQGAP1 contributes to the efficiency of the EGFR/PI3K signaling pathway in vivo .…”

“…Considering the importance of PI3K signaling in HNSCCs, we explored whether IQGAP1 plays a role in head and neck carcinogenesis using a well-validated mouse model that drives HNSCC using a synthetic oral carcinogen, 4-nitroquinoline 1-oxide (4NQO, [ 24 ]). After 4NQO treatment, Iqgap1 -/- mice developed significantly lower cancer incidences, lesser disease severity, and fewer cancer foci per mouse, when compared to the Iqgap1 +/+ mice [ 19 ]. Tumors arising in Iqgap1 -/- mice showed significantly lower levels of PI3K signaling than those in Iqgap1 +/+ mice, indicating that IQGAP1 contributes to HNSCC, at least in part, through PI3K signaling [ 19 ].…”