Targeting of several glycolytic enzymes using RNA interference reveals aldolase affects cancer cell proliferation through a non-glycolytic mechanism

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cancer cells exhibit increased glucose metabolism via the Warburg effect.
• Glycolytic enzymes are potential therapeutic targets for cancer treatment.
• Specific enzymes like aldolase A, GAPDH, TPI, and enolase 1 were previously untargeted.

Purpose of the Study:

• To investigate the role of four specific glycolytic enzymes in cancer cell proliferation using RNA interference.
• To identify novel therapeutic targets within the glycolytic pathway for cancer treatment.

Main Methods:

• RNA interference (RNAi) was used to knock down four glycolytic enzymes in Ras-transformed NIH-3T3 cells.
• Aldolase knockdown effects on cell proliferation, glycolytic flux, and ATP concentration were assessed.
• Rescue experiments were performed using exogenous aldolase and an enzymatically dead aldolase variant.

Main Results:

• Aldolase knockdown demonstrated the most significant inhibition of cancer cell proliferation (90%).
• The proliferation defect was rescued by expressing functional or F-actin-binding deficient aldolase, suggesting a non-metabolic role.
• Aldolase knockdown disrupted actin-cytoskeleton dynamics, leading to increased multinucleation, indicating a role in cell division.

Conclusions:

• Aldolase plays a crucial role in cancer cell proliferation, potentially through its interaction with the actin cytoskeleton rather than its metabolic function.
• Aldolase represents a promising therapeutic target for cancer treatment.
• Targeting aldolase may offer a novel strategy to inhibit cancer growth by disrupting cell division processes.