Proteomic analysis of proteins responsible for the development of doxorubicin resistance in human uterine cancer cells.
Drug resistance is a common cause of failure in cancer chemotherapy treatments. In this study, we used a pair of uterine sarcoma cancer lines, MES-SA, and the doxorubicin-resistant MES-SA/Dx5 as a model system to examine resistance-dependent cellular responses and to identify potential therapeutic targets. We used two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) to examine the global protein expression changes induced by doxorubicin treatment and doxorubicin resistance. A proteomic study revealed that doxorubicin-exposure altered the expression of 87 proteins in MES-SA cells, while no significant response occurred in similarly treated MES-SA/Dx5 cells, associating these proteins with drug specific resistance. By contrast, 37 proteins showed differential expression between MES-SA and MES-SA/Dx5, indicating baseline resistance. Further studies have used RNA interference, cell viability analysis, and analysis of apoptosis against asparagine synthetase (ASNS) and membrane-associated progesterone receptor component 1 (mPR) proteins, to monitor and evaluate their potency on the formation of doxorubicin resistance. The proteomic approach allowed us to identify numerous proteins, including ASNS and mPR, involved in various drug-resistance-forming mechanisms. Our results provide useful diagnostic markers and therapeutic candidates for the treatment of doxorubicin-resistant uterine cancer.
Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
Szu-Ting
ST
Lin
Hsiu-Chuan
HC
Chou
Shing-Jyh
SJ
Chang
Yi-Wen
YW
Chen
Ping-Chiang
PC
Lyu
Wen-Ching
WC
Wang
Margaret Dah-Tsyr
MD
Chang
Hong-Lin
HL
Chan
D017209:Apoptosis / Q000187:drug effects; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000235:genetics; D040901:Proteomics / Q000379:methods; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D012509:Sarcoma / Q000188:drug therapy*; D057825:Two-Dimensional Difference Gel Electrophoresis; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D008565:Membrane Proteins; D009363:Neoplasm Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D001217:Aspartate-Ammonia Ligase