ATM deficiency promotes progression of CRPC by enhancing Warburg effect

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• ATM is a key regulator of DNA double-strand break repair.
• PARP inhibitors exploit synthetic lethality in DNA repair-deficient cancers.
• ATM mutations are increasingly found in metastatic castration-resistant prostate cancer (mCRPC).

Purpose of the Study:

• To elucidate the molecular mechanisms by which ATM mutations drive CRPC progression.
• To investigate the role of metabolism in ATM-deficient CRPC.
• To identify potential therapeutic targets for ATM-mutant CRPC.

Main Methods:

• CRISPR/Cas9 gene editing to create ATM-deficient CRPC cells.
• Assessment of cell proliferation and xenograft tumor growth.
• Metabolic analysis, including the Warburg effect and glucose flux.
• Measurement of lactate dehydrogenase A (LDHA) expression and reactive oxygen species (ROS).
• Inhibition of LDHA using siRNA and small molecule inhibitors (FX11).

Main Results:

• ATM deficiency enhanced CRPC cell proliferation and tumor growth.
• ATM deficiency promoted the Warburg effect, increasing aerobic glycolysis.
• ATM deficiency upregulated LDHA, leading to increased lactate production and decreased mitochondrial ROS.
• Inhibition of LDHA reduced lactate, increased ROS, and potentiated cell death in ATM-deficient CRPC cells.

Conclusions:

• ATM mutation promotes CRPC progression through metabolic reprogramming, specifically enhanced aerobic glycolysis via LDHA upregulation.
• Targeting LDHA-mediated glycolysis presents a novel therapeutic strategy for ATM-mutant CRPC.
• This approach may offer an effective treatment for PARP inhibitor-resistant mCRPC.