Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance

• Published in: Toxicology and applied pharmacology Vol. 288; no. 3; pp. 359 - 373
• Main Authors: Lin, Chi-Chen, Chen, Jing-Ting, Lin, Meng-Wei, Chan, Chia-Hao, Wen, Yueh-Feng, Wu, Shin-Bei, Chung, Ting-Wen, Lyu, Kevin W., Chou, Hsiu-Chuan, Chan, Hong-Lin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Antigens - genetics; Antigens - metabolism; Antineoplastic Agents - pharmacology; BIOLOGICAL MARKERS; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; CARCINOMAS; Cell Line, Tumor - drug effects; Cell Survival - drug effects; DESORPTION; DIGE; Drug Resistance, Neoplasm; DRUGS; ELECTROPHORESIS; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gefitinib; GELS; Gene Silencing; Humans; IONIZATION; LASERS; Lung adenocarcinoma; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; LUNGS; MASS SPECTROSCOPY; Membrane Proteins - genetics; Membrane Proteins - metabolism; mPR; PCNT; PROGESTERONE; Proteomics; Proteomics - methods; Quinazolines - pharmacology; RECEPTORS; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Resistance; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Resistance; DIGE; Proteomics; Lung adenocarcinoma; Gefitinib; PCNT; mPR
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.08.008

Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12–18months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC. [Display omitted] •164 proteins associated with gefitinib resistance were identified through proteomic analysis.•In this study, a lung adenocarcinoma and its gefitinib resistant partner were established.•mPR and PCNT proteins have evidenced to play important roles in gefitinib resistance.