title: Akt Kinase-Interacting Protein 1 Signals through CREB to Drive Diffuse Malignant Mesothelioma.
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.
authors: Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Tadaaki
authors: T
authors: Yamada
authors: Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio.
authors: Joseph M
authors: JM
authors: Amann
authors: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Koji
authors: K
authors: Fukuda
authors: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors: Shinji
authors: S
authors: Takeuchi
authors: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Naoya
authors: N
authors: Fujita
authors: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors: Hisanori
authors: H
authors: Uehara
authors: Department of Respiratory Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan.
authors: Shotaro
authors: S
authors: Iwakiri
authors: Department of Respiratory Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan.
authors: Kazumi
authors: K
authors: Itoi
authors: Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio.
authors: Konstantin
authors: K
authors: Shilo
authors: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. david.carbone@osumc.edu syano@staff.kanazawa-u.ac.jp.
authors: Seiji
authors: S
authors: Yano
authors: Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio. david.carbone@osumc.edu syano@staff.kanazawa-u.ac.jp.
authors: David P
authors: DP
authors: Carbone
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000503:physiopathology; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C512283:CC2D1A protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D017868:Cyclic AMP-Dependent Protein Kinases