Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Gefitinib, an EGFR tyrosine kinase inhibitor, is a standard lung cancer treatment.
• Drug resistance to gefitinib leads to progressive disease in some patients.
• Ectopic translocation of ecto-adenosine triphosphate (ATP) synthase to the plasma membrane presents a potential therapeutic target in drug-resistant cells.

Purpose of the Study:

• To investigate the therapeutic potential of ecto-ATP synthase inhibition in gefitinib-resistant lung cancer.
• To elucidate the molecular mechanisms underlying ecto-ATP synthase inhibitor action.

Main Methods:

• Quantitative multi-omics profiling.
• Analysis of CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα).
• Assessment of long noncoding RNA (lncRNA) GAS5 expression.
• Investigation of the p53 pathway activation.
• GAS5-protein interactomic profiling.

Main Results:

• Ecto-ATP synthase inhibition increases DNA topoisomerase IIα (topo IIα) phosphorylation at serine 1106 via CK2.
• This inhibition also elevates the expression of the lncRNA GAS5.
• GAS5 associates with topo IIα, further enhancing its phosphorylation.
• The p53 pathway is activated downstream of GAS5, leading to programmed cell death.

Conclusions:

• Ecto-ATP synthase blockade is a viable therapeutic strategy for gefitinib-resistant lung cancer.
• The mechanism involves the CK2/phospho-topo IIα/GAS5 network.
• This approach regulates programmed cell death in resistant lung cancer cells.