title: Knockdown of cyclophilin A reverses paclitaxel resistance in human endometrial cancer cells via suppression of MAPK kinase pathways.
abstract: OBJECTIVE
  Paclitaxel resistance remains to be a major obstacle to the chemotherapy of endometrial cancer. Using proteomic-based approach, we used to identify cyclophilin A (CypA) as a potential therapeutic target for endometrial cancer. As a natural continuation, this study aimed to reveal the correlation between CypA and paclitaxel resistance and evaluate the possibility of CypA as a therapeutic target for reversal of resistance.
  
  
  METHODS
  Two paclitaxel-resistant endometrial cancer cell sublines HEC-1-B/TAX and AN3CA/TAX were generated, and expressions of CypA, P-gp, MRP-2 and survivin were demonstrated by Western blotting. CypA was knocked down by RNA interference, and the subsequent effects on the alteration of paclitaxel resistance were examined by MTT, flow cytometry and migratory/invasive transwell assays. MAPK kinases activities were examined by Western blotting.
  
  
  RESULTS
  CypA knockdown led to significant inhibition of cell proliferation, induction of apoptosis and suppression of migratory/invasive capacity in HEC-1-B/TAX and AN3CA/TAX cells when exposed to paclitaxel. CypA knockdown led to reductions in total and phosphorylated MAPK kinases, including Akt, ERK1/2, p38 MAPK and JNK, in HEC-1-B/TAX cells. Furthermore, pretreatment with MAPK kinase inhibitors exhibited a synergistic effect in combination with CypA knockdown.
  
  
  CONCLUSIONS
  These results demonstrated that CypA expression was up-regulated in paclitaxel-resistant cancer cells, and knockdown of CypA could reverse the paclitaxel resistance through, at least partly, suppression of MAPK kinase pathways, presenting a possibility of CypA serving as a therapeutic target to overcome paclitaxel resistance.
authors.affiliation: Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China, qingshanxiagu@tom.com.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Li
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Min
authors.forename: Jinhai
authors.initials: J
authors.lastname: Gou
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058990:Molecular Targeted Therapy; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C000715087:ABCC2 protein, human; D000972:Antineoplastic Agents, Phytogenic; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D021984:Cyclophilin A; D017239:Paclitaxel