TY - JOUR
T1 - A PI3K/AKT scaffolding protein, IQ motif–containing GTPase associating protein 1 (IQGAP1), promotes head and neck carcinogenesis
AU - Wei, Tao
AU - Choi, Suyong
AU - Buehler, Darya
AU - Anderson, Richard A.
AU - Lambert, Paul F.
N1 - Funding Information:
This study was supported by the following NIH grants: CA210807, CA022443, DE026787. This study made use of core facilities of the University of Wisconsin Carbone Cancer Center (NIH grant CA014520). The authors thank Professor Alan Rapraeger as well as other members of the Lambert lab for useful discussions. The author(s) thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520), and the Office of the Director— NIH (S10OD023526) for use of its facilities and services. The TMA analysis was supported by the Specialized Program of Research Excellence (SPORE) program, through the NIH National Institute of Dental and Craniofacial Research (NIDCR) and National Cancer Institute (NCI), grant P50DE026787.
Funding Information:
This study was supported by the following NIH grants: CA210807, CA022443, DE026787. This study made use of core facilities of the University of Wisconsin Carbone Cancer Center (NIH grant CA014520). The authors thank Professor Alan Rapraeger as well as other members of the Lambert lab for useful discussions. The author(s) thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520), and the Office of the Director?NIH (S10OD023526) for use of its facilities and services. The TMA analysis was supported by the Specialized Program of Research Excellence (SPORE) program, through the NIH National Institute of Dental and Craniofacial Research (NIDCR) and National Cancer Institute (NCI), grant P50DE026787.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-1063
DO - 10.1158/1078-0432.CCR-19-1063
M3 - Article
C2 - 31597661
AN - SCOPUS:85077476615
SN - 1078-0432
VL - 26
SP - 301
EP - 311
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -