PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Metabolism

Background:

• Polo-like kinase 1 (PLK1) is implicated in metabolic reprogramming, shifting cells from oxidative phosphorylation (OXPHOS) to glycolysis.
• The precise molecular mechanism by which PLK1 influences this metabolic switch remains largely undefined.
• Pyruvate dehydrogenase (PDH) is a key enzyme regulating the entry of pyruvate into the tricarboxylic acid (TCA) cycle.

Purpose of the Study:

• To elucidate the molecular mechanism of PLK1-driven metabolic reprogramming from OXPHOS to glycolysis.
• To investigate the role of PDHA1 phosphorylation at threonine 57 (PDHA1-T57) in this metabolic shift.
• To evaluate the therapeutic potential of combining a PLK1 inhibitor (Onvansertib) with a PDH kinase (PDK) inhibitor (dichloroacetic acid, DCA) for lung cancer treatment.

Main Methods:

• Stable-isotope resolved metabolomics (SIRM) to analyze metabolic flux.
• Generation of cell lines and transgenic mice mimicking PDHA1-T57 phosphorylation.
• In vivo and in vitro studies combining Onvansertib and DCA to assess synergistic effects on tumor growth.

Main Results:

• PLK1 phosphorylation of PDHA1-T57 promotes PDHA1 degradation and metabolic reprogramming from OXPHOS to glycolysis.
• Cells with PDHA1-T57 phosphorylation utilize the aspartate-malate shuttle over glucose-derived pyruvate for TCA cycle sustenance.
• Combined treatment with Onvansertib and DCA synergistically inhibited lung tumor growth, enhanced mitochondrial reactive oxygen species (ROS), reduced glycolysis, and induced apoptosis.

Conclusions:

• PLK1-mediated PDHA1 phosphorylation is a key driver of metabolic reprogramming in lung carcinogenesis.
• Targeting PLK1 and PDK simultaneously presents a promising therapeutic strategy for lung cancer.
• Results support clinical trials evaluating Onvansertib plus DCA for lung cancer treatment.