Multi‐kinase framework promotes proliferation and invasion of lung adenocarcinoma through activation of dynamin‐related protein 1

• Published in: Molecular Oncology Vol. 15; no. 2; pp. 560 - 578
• Main Authors: Chung, Kuei‐Pin, Huang, Yen‐Lin, Chen, Yi‐Jung, Juan, Yi‐Hsiu, Hsu, Chia‐Lang, Nakahira, Kiichi, Huang, Yen‐Tsung, Lin, Mong‐Wei, Wu, Shang‐Gin, Shih, Jin‐Yuan, Chang, Yih‐Leong, Yu, Chong‐Jen
• Format: Journal Article
• Language: English
• Published: United States Wiley 01.02.2021; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: Acidification; Adenocarcinoma; Adenocarcinoma of Lung; Adenosine; Adenosine kinase; AKT protein; AMP; Animals; Atrophy; Breast cancer; Cancer; Cell culture; Cell cycle; Cell Line, Tumor; Cell Proliferation; CRISPR; cyclin‐dependent kinase 2; Deoxyribonucleic acid; DNA; DNA-directed RNA polymerase; Dynamin; Dynamins; dynamin‐related protein 1; Environmental effects; Epidermal growth factor; Epidermal growth factor receptors; Extracellular signal-regulated kinase; Female; Gene expression; Genomes; glycolytic serine synthesis; Hepatocellular carcinoma; Hospitals; Humans; Immunohistochemistry; Kinases; lung adenocarcinoma; Lung cancer; Lung Neoplasms; Male; Medical prognosis; Medical research; Mesenchyme; Metabolism; Mice; Mice, Knockout; Mice, Nude; mitochondria; Mitochondrial DNA; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Oxidative phosphorylation; Pathogenesis; Polyesters; Polymerase chain reaction; Population studies; prognosis; Protein Kinases; Proteins; RC254-282; Reagents; Survival; Therapeutic targets; Utrophin; United States > US; dynamin-related protein 1; prognosis; cyclin-dependent kinase 2; mitochondria; lung adenocarcinoma; glycolytic serine synthesis
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12843

Here, we demonstrated that the multikinase framework including ERK/AKT and CDK2 promotes the proliferation and invasion of lung adenocarcinoma cell lines through activating DRP1. Our results further uncovered the prognostic significance of DRP1 in early‐stage lung adenocarcinoma, showing that the expression and activation of DRP1 are both significantly associated with an increased risk of postoperative recurrence. Recent studies revealed the role of dynamin‐related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function, and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of postoperative recurrence in stage I to stage IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, the proliferation and invasion are both suppressed in DRP1‐depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of postoperative recurrence in early‐stage lung adenocarcinoma.