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Cancer Res. 2015 Oct 1;75(19):4188-97. doi: 10.1158/0008-5472.CAN-15-0858. Epub 2015 Aug 20.

Akt Kinase-Interacting Protein 1 Signals through CREB to Drive Diffuse Malignant Mesothelioma.

Author information

1
Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
2
Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio.
3
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
4
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
5
Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
6
Department of Respiratory Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan.
7
Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio.
8
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. david.carbone@osumc.edu syano@staff.kanazawa-u.ac.jp.
9
Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio. david.carbone@osumc.edu syano@staff.kanazawa-u.ac.jp.

Abstract

Diffuse malignant mesothelioma (DMM) is a tumor of serosal membranes with propensity for progressive local disease. Because current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve the outcomes of patients with this disease. Akt kinase interacting protein 1 (Aki1; Freud-1/CC2D1A) is a scaffold protein for the PI3K-PDK1-Akt signaling module that helps determine receptor signal selectivity for EGFR. Aki1 has been suggested as a therapeutic target, but its potential has yet to be evaluated in a tumor setting. Here, we report evidence supporting its definition as a therapeutic target in DMM. In cell-based assays, Aki1 silencing decreased cell viability and caused cell-cycle arrest of multiple DMM cell lines via effects on the PKA-CREB1 signaling pathway. Blocking CREB activity phenocopied Aki1 silencing. Clinically, Aki1 was expressed in most human DMM specimens where its expression correlated with phosphorylated CREB1. Notably, Aki1 siRNA potently blocked tumor growth in an orthotopic implantation model of DMM when administered directly into the pleural cavity of tumor-bearing mice. Our findings suggest an important role for the Aki1-CREB axis in DMM pathogenesis and provide a preclinical rationale to target Aki1 by intrathoracic therapy in locally advanced tumors.

PMID:
26294214
DOI:
10.1158/0008-5472.CAN-15-0858
[Indexed for MEDLINE]
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