Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network
Journal
Molecular and Cellular Proteomics
Journal Volume
19
Journal Issue
11
Pages
1805-1825
Date Issued
2020
Author(s)
Abstract
The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIa (topo IIa) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIa and subsequently enhancing the phosphorylation level of topo IIa. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIa/GAS5 network in gefitinib-resistant lung cancer cells. ? 2020 Chang et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
4,5,6,7 tetrabromobenzimidazole; antineoplastic agent; benzimidazole derivative; casein kinase II; citreoviridin; DNA topoisomerase (ATP hydrolysing) A; gefitinib; growth arrest specific protein 5; long untranslated RNA; protein p53; protein serine threonine kinase inhibitor; proton transporting adenosine triphosphate synthase; proton transporting adenosine triphosphate synthase inhibitor; serine; unclassified drug; antineoplastic agent; casein kinase II; DNA topoisomerase (ATP hydrolysing); GAS5 long non-coding RNA, human; gefitinib; long untranslated RNA; protein kinase inhibitor; protein p53; proton transporting adenosine triphosphatase; small interfering RNA; TP53 protein, human; antineoplastic activity; apoptosis; Article; cell membrane; controlled study; data analysis software; enzyme phosphorylation; gene expression; human; human cell; inner membrane; interactomics; lung cancer; mitochondrial membrane; multiomics; phosphoproteomics; priority journal; quantitative analysis; signal transduction; transcriptomics; apoptosis; cell proliferation; cell survival; DNA microarray; drug effect; drug resistance; gene ontology; genetics; immunohistochemistry; lung tumor; metabolism; non small cell lung cancer; phosphorylation; proteomics; tandem mass spectrometry; tumor cell line; Antineoplastic Agents; Apoptosis; ATP Synthetase Complexes; Carcinoma, Non-Small-Cell Lung; Casein Kinase II; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cell Survival; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; Gefitinib; Gene Ontology; Humans; Immunohistochemistry; Lung Neoplasms; Oligonucleotide Array Sequence Analysis; Phosphorylation; Protein Kinase Inhibitors; Proteomics; RNA, Long Noncoding; RNA, Small Interfering; Signal Transduction; Tandem Mass Spectrometry; Tumor Suppressor Protein p53
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Type
journal article