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, Alexander Hergovich

Research output: Contribution to journalArticle

9 Scopus citations

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 anchorageindependent growth of Ras-transformed human cells, while knockdown of USP30, a negative regulator of PINK1/Parkin-mediated mitophagy, restored anchorageindependent growth of STK38-depleted Ras-transformed human cells. Therefore, our findings collectively reveal novel molecular players that determine whether Rastransformed human cells die or survive upon cell detachment, which potentially could be exploited for the development of novel strategies to target Ras-transformed cells.

Original languageEnglish (US)
Pages (from-to)44142-44160
Number of pages19
JournalOncotarget
Volume7
Issue number28
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Cellular transformation
  • Mitophagy
  • Ras GTPase
  • STK38
  • Selective autophagy

ASJC Scopus subject areas

  • Oncology

Cite this

Bettoun, A., Joffre, C., Zago, G., Surdez, D., Vallerand, D., Gundogdu, R., Sharif, A. A. D., Gomez, M., Cascone, I., Meunier, B., White, M. A., Codogno, P., Parrini, M. C., Camonis, J. H., & Hergovich, A. (2016). Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation. Oncotarget, 7(28), 44142-44160. https://doi.org/10.18632/oncotarget.9875