Overexpression of optic atrophy 1 protein increases cisplatin resistance via inactivation of caspase-dependent apoptosis in lung adenocarcinoma cells

• Published in: Human pathology 2012, Vol.43 (1), p.105-114
• Main Authors: Fang, Hsin-Yuan, MD, Chen, Chih-Yi, MD, Chiou, Shiow-Her, PhD, Wang, Yu-Ting, MSc, Lin, Tze-Yi, MD, PhD, Chang, Hui-Wen, MD, Chiang, I-Ping, MD, Lan, Kuo-Jung, BSc, Chow, Kuan-Chih, PhD
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - diagnosis; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; Biological and medical sciences; Cancer therapies; Caspase; Caspase Inhibitors; Caspases - metabolism; Cell cycle; Cell Line, Tumor; Cisplatin - pharmacology; Cytochrome c; Deoxyribonucleic acid; Diseases of visual field, optic nerve, optic chiasma and optic tracts; DNA; DNA repair; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Investigative techniques, diagnostic techniques (general aspects); Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Male; Medical sciences; Mitochondria; Mitochondrial membrane; Mortality; Neoplasm Staging; Ophthalmology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pneumology; Proteins; RNA, Messenger - metabolism; Smoking; Statistical analysis; Survival Rate; Taiwan - epidemiology; Tumors of the respiratory system and mediastinum
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2011.04.012

Summary Optic atrophy 1 protein, a 112-kd guanosine triphosphatase, is involved in the mitochondrial inner membrane fusion and anticancer drug-mediated cytotoxicity, which implicate an association with disease progression of the cancer. In this study, we investigated the prognostic value of optic atrophy 1 expression in patients with lung adenocarcinoma. Using immunohistochemical staining, expression of optic atrophy 1 was determined in 286 lung adenocarcinoma patients. Expression of optic atrophy 1 was confirmed by immunoblotting. The relationship between optic atrophy 1 expression and clinicopathological parameters was analyzed statistically by comparing survival between different groups using the log-rank test. The results showed that optic atrophy 1 overexpression was detected in 219 (76.6%) of lung adenocarcinoma patients. A significant difference was found in cumulative survival between patients with high optic atrophy 1 levels and those with low optic atrophy 1 levels ( P = .0016). In the in vitro experiments with cell lines, silencing of optic atrophy 1 expression reduced cisplatin resistance, which was further shown via increased release of cytochrome c and activation of caspase-dependent apoptotic pathway. In conclusion, optic atrophy 1 is highly expressed in lung adenocarcinoma and indicates poor prognosis.