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Published on: July 17, 2018
PLA2R1 kills cancer cells by inducing mitochondrial stress
Arnaud Augert1, David Vindrieux2, Christophe A Girard3
1INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon F-69373, France; Centre Léon Bérard, Lyon F-69373, France; Université de Lyon, Lyon F-69373, France; UMR8161, Institut de Biologie de Lille, CNRS/Universités de Lille 1 et 2, Lille F-5900, France.
Abstract:
Little is known about the biological functions of the phospholipase A2 receptor (PLA2R1) except that it has the ability to bind a few secreted phospholipases A2 (sPLA2's). We have previously shown that PLA2R1 regulates senescence in normal human cells. In this study, we investigated the ability of PLA2R1 to control cancer cell growth. Analysis of expression in cancer cells indicates a marked PLA2R1 decrease in breast cancer cell lines compared to normal or nontransformed human mammary epithelial cells. Accordingly, PLA2R1 ectopic expression in PLA2R1-negative breast cancer cell lines led to apoptosis, whereas a prosenescence response was predominantly triggered in normal cells. PLA2R1 structure-function studies and the use of chemical inhibitors of sPLA2-related signaling pathways suggest that the effect of PLA2R1 is sPLA2-independent. Functional experiments demonstrate that PLA2R1 regulation of cell death is driven by a reactive oxygen species (ROS)-dependent mechanism. While screening for ROS-producing complexes involved in PLA2R1 biological responses, we identified a critical role for the mitochondrial electron transport chain in PLA2R1-induced ROS production and cell death. Taken together, this set of data provides evidence for an important role of PLA2R1 in controlling cancer cell death by influencing mitochondrial biology.
Insights
The phospholipase A2 receptor (PLA2R1) controls cancer cell death by impacting mitochondrial reactive oxygen species (ROS) production. Its reduced expression in breast cancer suggests a role in tumor suppression via apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The biological functions of phospholipase A2 receptor (PLA2R1) are largely unknown, beyond its binding of secreted phospholipases A2 (sPLA2s).
- Previous research demonstrated PLA2R1's role in regulating senescence in normal human cells.
Purpose of the Study:
- To investigate the role of PLA2R1 in controlling cancer cell growth.
- To elucidate the mechanisms underlying PLA2R1's function in cancer cells.
Main Methods:
- Analysis of PLA2R1 expression in breast cancer cell lines and normal mammary epithelial cells.
- Ectopic expression of PLA2R1 in cancer cells.
- Structure-function studies of PLA2R1.
- Investigation of sPLA2-related signaling pathways.
- Functional experiments assessing cell death mechanisms, including reactive oxygen species (ROS) production and mitochondrial electron transport chain activity.
Main Results:
- PLA2R1 expression is significantly decreased in breast cancer cell lines compared to normal cells.
- Ectopic expression of PLA2R1 induced apoptosis in cancer cells and senescence in normal cells.
- PLA2R1's effect on cell death is independent of sPLA2 signaling.
- Cell death regulation by PLA2R1 is mediated by ROS production.
- The mitochondrial electron transport chain is critical for PLA2R1-induced ROS production and cell death.
Conclusions:
- PLA2R1 plays a crucial role in controlling cancer cell death.
- PLA2R1 influences cancer cell fate through a ROS-dependent mechanism involving mitochondrial biology.
- Reduced PLA2R1 expression may contribute to breast cancer development.
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