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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Survival
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mesothelioma / metabolism*
  • Mesothelioma / pathology
  • Mice
  • Mice, SCID
  • Neoplasm Proteins / physiology*
  • Neoplasm Transplantation
  • Phosphorylation
  • Pleural Neoplasms / physiopathology
  • Protein Processing, Post-Translational
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • Transcription, Genetic

Substances

  • CC2D1A protein, human
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Cyclic AMP-Dependent Protein Kinases

Supplementary concepts

  • Mesothelioma, Malignant