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Published on: March 31, 2023
Targeting a moonlighting function of aldolase induces apoptosis in cancer cells
Agnieszka Gizak1, Janusz Wiśniewski1, Paul Heron2
1Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, 50-335, Poland.
Abstract:
Muscle fructose-1,6-bisphosphate aldolase (ALDOA) is among the most abundant glycolytic enzymes in all cancer cells. Here, we show that the enzyme plays a previously unknown and critical role in a cancer cell survival. Simultaneous inhibition of ALDOA activity and interaction with F-actin cytoskeleton using ALDOA slow-binding inhibitor UM0112176 leads to a rapid cofilin-dependent loss of F-actin stress fibers which is associated with elevated ROS production, inhibition of ATP synthesis, increase in calcium levels, caspase activation and arrested cellular proliferation. These effects can be reproduced by silencing of ALDOA. The mechanism of pharmacological action is, however, independent of the catalytic function of the enzyme, specific to cancer cells, and is most deleterious to cells undergoing the epithelial-mesenchymal transition, a process facilitating cancer cell invasion. Our results demonstrate that the overabundance of ALDOA in cancer cells is associated with its moonlighting rather than catalytic functions. This may have significant implications for development of novel broad-based anti-cancer therapies.
Insights
Muscle fructose-1,6-bisphosphate aldolase (ALDOA), an abundant enzyme, plays a critical role in cancer cell survival. Inhibiting ALDOA and its actin interaction halts cancer proliferation and invasion, suggesting novel therapeutic targets.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Muscle fructose-1,6-bisphosphate aldolase (ALDOA) is highly abundant in cancer cells.
- ALDOA's role in cancer cell survival is not fully understood.
- The epithelial-mesenchymal transition (EMT) is crucial for cancer invasion.
Purpose of the Study:
- To investigate the non-catalytic functions of ALDOA in cancer cell survival.
- To explore the potential of targeting ALDOA for anti-cancer therapies.
- To elucidate the mechanism by which ALDOA inhibition affects cancer cells.
Main Methods:
- Utilized ALDOA slow-binding inhibitor UM0112176 to inhibit ALDOA activity and F-actin interaction.
- Assessed effects on F-actin stress fibers, reactive oxygen species (ROS) production, ATP synthesis, calcium levels, and caspase activation.
- Employed ALDOA gene silencing to confirm findings.
- Examined cancer cells undergoing EMT.
Main Results:
- Inhibition of ALDOA and its F-actin interaction led to rapid, cofilin-dependent loss of F-actin stress fibers.
- Observed elevated ROS, inhibited ATP synthesis, increased calcium, caspase activation, and arrested proliferation.
- These effects were reproduced by ALDOA silencing.
- The mechanism was independent of ALDOA's catalytic function and specific to cancer cells, particularly those in EMT.
Conclusions:
- ALDOA's overabundance in cancer cells is linked to its moonlighting functions, not just catalysis.
- Targeting ALDOA's non-catalytic roles offers a novel therapeutic strategy for broad-spectrum anti-cancer treatments.
- ALDOA inhibition is particularly effective against invasive cancer cells undergoing EMT.
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