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The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action

A Griveau1,2,3,4, G Devailly1,2,3,4, L Eberst1,2,3,4

  • 1Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

Oncogene
|April 5, 2016
PubMed

Insights

The phospholipase A2 receptor (PLA2R1) promotes tumor suppression by increasing mitochondrial content via the JAK2-ERRα pathway. This pathway regulates mitochondrial biogenesis and function, ultimately inhibiting tumor growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The biological role of phospholipase A2 receptor (PLA2R1) is not well understood.
  • PLA2R1 is implicated in tumor suppression through JAK2 activation, but mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PLA2R1 mediates tumor suppression.
  • To investigate the role of mitochondrial regulation in PLA2R1-induced oncosuppression.

Main Methods:

  • Assessed mitochondrial content by measuring mitochondrial proteins, cardiolipin, and mitochondrial DNA (mtDNA).
  • Investigated the role of estrogen-related receptor alpha1 (ERRα) and JAK2 signaling.
  • Evaluated the impact of blocking the ERRα-controlled mitochondrial program on PLA2R1 function.

Main Results:

  • PLA2R1 significantly increases mitochondrial content, including mtDNA and TFAM levels.
  • PLA2R1 upregulates ERRα expression and its downstream mitochondrial targets via JAK2.
  • Downregulation of PLA2R1 reduces ERRα levels and mitochondrial biogenesis.
  • Inhibition of the ERRα-mediated mitochondrial program abrogates PLA2R1's tumor-suppressive effects.

Conclusions:

  • PLA2R1 enhances mitochondrial biogenesis and function through the JAK2-ERRα signaling axis.
  • ERRα and its mitochondrial program are key downstream effectors of PLA2R1 in tumor suppression.
  • The PLA2R1-JAK2-ERRα pathway represents a novel mechanism for oncosuppression.

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