title: Plk1 phosphorylation of orc2 and hbo1 contributes to gemcitabine resistance in pancreatic cancer.
abstract: Although gemcitabine is the standard chemotherapeutic drug for treatment of pancreatic cancer, almost all patients eventually develop resistance to this agent. Previous studies identified Polo-like kinase 1 (Plk1) as the mediator of gemcitabine resistance, but the molecular mechanism remains unknown. In this study, we show that Plk1 phosphorylation of Orc2 and Hbo1 mediates the resistance to gemcitabine. We show that the level of Plk1 expression positively correlates with gemcitabine resistance, both in pancreatic cancer cells and xenograft tumors. Overexpression of Plk1 increases gemcitabine resistance, while inhibition of Plk1 sensitizes pancreatic cancer cells to gemcitabine treatment. To validate our findings, we show that inhibition of Plk1 sensitizes tumors to gemcitabine treatment in a mouse xenograft study. Mechanistically, we find that Plk1 phosphorylation of Orc2 maintains DNA replication on gemcitabine treatment. Furthermore, Plk1 phosphorylation of Hbo1 transcriptionally increases cFos expression and consequently elevates its target multidrug resistance 1 (MDR1), which was previously reported to confer chemotherapeutic drug resistance. Knockdown of cFos or MDR1 sensitizes gemcitabine-resistant cells to gemcitabine treatment. Finally, pancreatic cancer cells expressing Plk1-unphosphorylatable mutants of Orc2 or Hbo1 are more sensitive to gemcitabine than cells expressing wild-type Orc2 or Hbo1. In short, our study provides a mechanism for Plk1-mediated gemcitabine resistance, suggesting that Plk1 is a promising target for treatment of gemcitabine-resistant pancreatic cancer.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Song
authors.forename: X Shawn
authors.initials: XS
authors.lastname: Liu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Rice
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.forename: Bennett D
authors.initials: BD
authors.lastname: Elzey
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
authors.forename: Tony
authors.initials: T
authors.lastname: Hazbun
authors.forename: Elena G
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D051738:Origin Recognition Complex / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D051548:Histone Acetyltransferases; D051738:Origin Recognition Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011621:Pteridines; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C497224:ORC2 protein, human; C496553:KAT7 protein, human