Glycolysis maintains AMPK activation in sorafenib-induced Warburg effect

Area of Science:

• Oncology
• Metabolic pathways
• Cancer resistance mechanisms

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer death with limited curative options.
• Sorafenib, a first-line HCC treatment, induces resistance via aerobic glycolysis (Warburg effect).
• AMP-activated protein kinase (AMPK) regulates metabolism and is crucial for sorafenib resistance, but its activation dynamics are poorly understood.

Purpose of the Study:

• To investigate the activation dynamics and regulation of AMPK in HCC during sorafenib treatment.
• To elucidate the role of glucose metabolism in modulating AMPK activation duration and its impact on therapeutic resistance.

Main Methods:

• Development and utilization of an AMPK activity biosensor for high-throughput, single-cell monitoring.
• Observation of AMPK activation in HCC cells under sorafenib treatment with varying glucose concentrations.
• Manipulation of glycolysis levels to assess their effect on AMPK activation duration.

Main Results:

• Sorafenib induces a transient activation of AMPK in HCC cells.
• The duration of AMPK activation is significantly dependent on glucose availability and glycolysis.
• Inhibiting glycolysis shortens AMPK activation, while increasing glycolysis prolongs it.

Conclusions:

• The duration of AMPK activation, rather than just its presence, is critical for cancer cells to evade therapeutic treatments like sorafenib.
• Glycolysis plays a key regulatory role in determining the duration of AMPK activation in HCC.
• Targeting glycolysis may represent a viable strategy to overcome sorafenib resistance in HCC by modulating AMPK activation dynamics.