title: Gemcitabine Enhances Kras-MEK-Induced Matrix Metalloproteinase-10 Expression Via Histone Acetylation in Gemcitabine-Resistant Pancreatic Tumor-initiating Cells.
abstract: Advanced pancreatic ductal adenocarcinoma is resistant to systemic chemotherapy, resulting in a poor prognosis. We previously isolated a human pancreatic tumor-initiating cell line, KMC07, from a patient with acquired resistance to gemcitabine chemotherapy. To improve the anticancer effects of gemcitabine, we investigated the molecular mechanism of KMC07 cells' resistance to gemcitabine.
  
  
  
  KMC07 cells were treated with gemcitabine, then gene expression and functional analyses performed using microarray, the quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, chromatin immunoprecipitation, and cell transplantation into nude mice.
  
  
  
  KMC07 cells, but not BxPC-3, PANC-1, MIA PaCa-2, or AsPC-1 cells, expressed matrix metalloproteinase-10 mRNA, the expression level of which was enhanced by gemcitabine. KMC07 cells were shown to carry a constitutively active Kras mutation, and a MEK inhibitor suppressed matrix metalloproteinase-10 mRNA expression. Gemcitabine enhanced histone H3 acetylation at the matrix metalloproteinase-10 promoter, and a histone acetyltransferase inhibitor reduced gemcitabine-enhanced matrix metalloproteinase-10 mRNA expression. Gemcitabine induced expression of matrix metalloproteinase-10 protein in KMC07-derived pancreatic tumors in vivo.
  
  
  
  We demonstrated constitutive activation of the Kras-MEK matrix metalloproteinase-10 signaling pathway in KMC07 cells that was enhanced by gemcitabine through histone acetylation. Our results may provide novel insights into gemcitabine-based treatment for gemcitabine-resistant pancreatic ductal adenocarcinoma.
authors.affiliation: From the *Department of Internal Medicine, Kobe Medical Center; and †Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimizu
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hori
mesh_terms: D000107:Acetylation; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D053506:Matrix Metalloproteinase 10 / Q000235:genetics* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D006657:Histones; C117307:KRAS protein, human; D003841:Deoxycytidine; D020930:MAP Kinase Kinase Kinases; D053506:Matrix Metalloproteinase 10; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine