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  • The EMBO Journal (2008) 27, 2181 - 2193
  • doi:10.1038/emboj.2008.149

Published online: 24 July 2008

Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis

Jayashree Joshi1,a, Pablo J Fernandez-Marcos2,a, Anita Galvez1, Ramars Amanchy1, Juan F Linares1, Angeles Duran1, Peterson Pathrose1, Michael Leitges3, Marta Cañamero2, Manuel Collado2, Clara Salas4, Manuel Serrano2, Jorge Moscat1 and Maria T Diaz-Meco1

  1. Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
  2. Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid, Spain
  3. The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
  4. Department of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain

Correspondence to:

Jorge Moscat, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267, USA. Tel.: +1 513 558 8419; Fax: +1 513 558 5061; E-mail: jorge.moscat@uc.edu

Maria T Diaz-Meco, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267, USA. Tel.: +1 513 558 8419; Fax: +1 513 558 5061; E-mail: maria.diazmeco@uc.edu

aThese authors contributed equally to this work

Received 14 April 2008; Accepted 7 July 2008

The atypical PKC-interacting protein, Par-4, inhibits cell survival and tumorigenesis in vitro, and its genetic inactivation in mice leads to reduced lifespan, enhanced benign tumour development and low-frequency carcinogenesis. Here, we demonstrate that Par-4 is highly expressed in normal lung but reduced in human lung cancer samples. We show, in a mouse model of lung tumours, that the lack of Par-4 dramatically enhances Ras-induced lung carcinoma formation in vivo, acting as a negative regulator of Akt activation. We also demonstrate in cell culture, in vivo, and in biochemical experiments that Akt regulation by Par-4 is mediated by PKCzeta, establishing a new paradigm for Akt regulation and, likely, for Ras-induced lung carcinogenesis, wherein Par-4 is a novel tumour suppressor.

  • Keywords:

    • Akt,
    • lung cancer,
    • NF-kappaB,
    • Par-4,
    • PKCzeta,
    • Ras