Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation.
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.
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Audrey
A
Bettoun
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.|Present address: Cancer Research Center of Toulouse, UMR1037, Toulouse, 31100, France.
Carine
C
Joffre
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Giulia
G
Zago
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Didier
D
Surdez
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
David
D
Vallerand
University College London, Cancer Institute, London, WC1E 6BT, United Kingdom.
Ramazan
R
Gundogdu
University College London, Cancer Institute, London, WC1E 6BT, United Kingdom.
Ahmad A D
AA
Sharif
University College London, Cancer Institute, London, WC1E 6BT, United Kingdom.
Marta
M
Gomez
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Ilaria
I
Cascone
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Brigitte
B
Meunier
University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA.
Michael A
MA
White
Inserm U1151-CNRS UMR 8253, Institut Necker Enfants-Malades, Paris, 75993, France.
Patrice
P
Codogno
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Maria Carla
MC
Parrini
Institut Curie, Inserm U830, Paris Sciences et Lettres University Paris, 75248, France.
Jacques H
JH
Camonis
University College London, Cancer Institute, London, WC1E 6BT, United Kingdom.
Alexander
A
Hergovich
D000818:Animals; D023102:Anoikis / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008819:Mice, Nude; D063306:Mitophagy / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human; D018631:ras Proteins
Ras GTPase; STK38; cellular transformation; mitophagy; selective autophagy