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Updated: Feb 14, 2026
Quantitative Measurement of Invadopodia-mediated Extracellular Matrix Proteolysis in Single and Multicellular Contexts
Published on: August 27, 2012
RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells
Mark A Hawk1, Cassandra L Gorsuch1, Patrick Fagan1
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Abstract:
For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5. As a consequence of mitophagy, ECM-detached cells experience diminished NADPH production in the mitochondria, and the subsequent elevation in ROS levels leads to non-apoptotic death. Furthermore, we find that antagonizing RIPK1/PGAM5 enhances tumour formation in vivo. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells.
Insights
Receptor-interacting protein kinase 1 (RIPK1) promotes cancer cell death upon extracellular matrix detachment by inducing mitophagy. Inhibiting this pathway enhances tumor formation, suggesting RIPK1 as a therapeutic target.
Area of Science:
- Cell biology
- Cancer research
- Metabolism
Background:
- Cancer cells must overcome anoikis and metabolic stress during extracellular matrix (ECM) detachment.
- Non-apoptotic cell death in ECM-detached cells is linked to reactive oxygen species (ROS), but mechanisms are unclear.
Purpose of the Study:
- To investigate the role of receptor-interacting protein kinase 1 (RIPK1) in regulating ROS and cell viability during ECM detachment.
- To elucidate the molecular mechanisms linking RIPK1, mitophagy, and cell death in detached cancer cells.
Main Methods:
- Investigated RIPK1 activation in ECM-detached cancer cells.
- Assessed the role of the mitochondrial phosphatase PGAM5 in RIPK1-mediated mitophagy.
- Measured mitochondrial NADPH production and ROS levels.
- Evaluated tumor formation in vivo after antagonizing RIPK1/PGAM5.
Main Results:
- RIPK1 activation during ECM detachment induces mitophagy via PGAM5.
- Mitophagy leads to decreased mitochondrial NADPH and increased ROS, causing non-apoptotic cell death.
- Inhibition of RIPK1/PGAM5 signaling promotes tumor formation in vivo.
Conclusions:
- RIPK1-induced mitophagy is a critical pathway regulating cancer cell survival or death during ECM detachment.
- Targeting the RIPK1/PGAM5-mitophagy axis offers a potential therapeutic strategy against ECM-detached cancer cells.
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