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

Chi-Chen Lin; Jing-Ting Chen; Meng-Wei Lin; Chia-Hao Chan; Yueh-Feng Wen; Shin-Bei Wu; Ting-Wen Chung; Kevin W Lyu; Hsiu-Chuan Chou; Hong-Lin Chan

doi:10.1016/j.taap.2015.08.008

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

Toxicol Appl Pharmacol. 2015 Nov 1;288(3):359-73. doi: 10.1016/j.taap.2015.08.008. Epub 2015 Aug 20.

Authors

Affiliations

¹ Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan; Institute of Biomedical Science, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taiwan; Department of Medical Research and Education, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
² Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
³ Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan.
⁴ Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan.
⁵ Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan.
⁶ Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan.
⁷ Lutheran Medical Center, Brooklyn, NY, USA; Global Scholars Program, St. George's University/Northumbria University, Newcastle upon Tyne, United Kingdom.
⁸ Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan. Electronic address: chouhc@mail.nhcue.edu.tw.
⁹ Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: hlchan@life.nthu.edu.tw.

PMID: 26298006
DOI: 10.1016/j.taap.2015.08.008

Abstract

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 12-18 months 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.

Keywords: DIGE; Gefitinib; Lung adenocarcinoma; PCNT; Proteomics; Resistance; mPR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Adenocarcinoma of Lung
Antigens / genetics
Antigens / metabolism
Antineoplastic Agents / pharmacology
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology*
Cell Line, Tumor / drug effects
Cell Survival / drug effects
Drug Resistance, Neoplasm*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Gefitinib
Gene Silencing
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Membrane Proteins / genetics
Membrane Proteins / metabolism
Proteomics / methods
Quinazolines / pharmacology*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Receptors, Progesterone / genetics
Receptors, Progesterone / metabolism
Signal Transduction
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

Antigens
Antineoplastic Agents
Membrane Proteins
PGRMC1 protein, human
Quinazolines
RNA, Small Interfering
Receptors, Progesterone
pericentrin
EGFR protein, human
ErbB Receptors
Gefitinib