Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:22870.

Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation

Audrey Bettoun _, Carine Joffre, Giulia Zago, Didier Surdez, David Vallerand, Ramazan Gundogdu, Ahmad A.D. Sharif, Marta Gomez, Ilaria Cascone, Brigitte Meunier, Michael A. White, Patrice Codogno, Maria Carla Parrini, Jacques H. Camonis and Alexander Hergovich

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Oncotarget. 2016; 7:44142-44160. https://doi.org/10.18632/oncotarget.9875

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Abstract

Audrey Bettoun1, Carine Joffre1,5,*, Giulia Zago1,*, Didier Surdez1, David Vallerand1, Ramazan Gundogdu2, Ahmad A.D. Sharif2, Marta Gomez2, Ilaria Cascone1, Brigitte Meunier1, Michael A. White3, Patrice Codogno4, Maria Carla Parrini1, Jacques H. Camonis1, Alexander Hergovich2

1Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France

2University College London, Cancer Institute, London, WC1E 6BT, United Kingdom

3University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA

4Inserm U1151-CNRS UMR 8253, Institut Necker Enfants-Malades, Paris, 75993, France

5Present address: Cancer Research Center of Toulouse, UMR1037, Toulouse, 31100, France

*These authors have contributed equally to this work

Correspondence to:

Alexander Hergovich, email: a.hergovich@ucl.ac.uk

Jacques H. Camonis, email: jacquescamonis@gmail.com

Keywords: Ras GTPase, STK38, selective autophagy, mitophagy, cellular transformation

Received: December 08, 2015    Accepted: May 12, 2016    Published: June 7, 2016

ABSTRACT

Oncogenic Ras signalling occurs frequently in many human cancers. However, no effective targeted therapies are currently available to treat patients suffering from Ras-driven tumours. Therefore, it is imperative to identify downstream effectors of Ras signalling that potentially represent promising new therapeutic options. Particularly, considering that autophagy inhibition can impair the survival of Ras-transformed cells in tissue culture and mouse models, an understanding of factors regulating the balance between autophagy and apoptosis in Ras-transformed human cells is needed. Here, we report critical roles of the STK38 protein kinase in oncogenic Ras transformation. STK38 knockdown impaired anoikis resistance, anchorage-independent soft agar growth, and in vivo xenograft growth of Ras-transformed human cells. Mechanistically, STK38 supports Ras-driven transformation through promoting detachment-induced autophagy. Even more importantly, upon cell detachment STK38 is required to sustain the removal of damaged mitochondria by mitophagy, a selective autophagic process, to prevent excessive mitochondrial reactive oxygen species production that can negatively affect cancer cell survival. Significantly, knockdown of PINK1 or Parkin, two positive regulators of mitophagy, also impaired anoikis resistance and anchorage-independent growth of Ras-transformed human cells, while knockdown of USP30, a negative regulator of PINK1/Parkin-mediated mitophagy, restored anchorage-independent growth of STK38-depleted Ras-transformed human cells. Therefore, our findings collectively reveal novel molecular players that determine whether Ras-transformed human cells die or survive upon cell detachment, which potentially could be exploited for the development of novel strategies to target Ras-transformed cells.


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