title: Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.
abstract: Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat due, in part, to de novo and acquired chemoresistance and radioresistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype, which is reminiscent of "cancer stem-like cells"; however, the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study shows that Notch-2 and its ligand, Jagged-1, are highly up-regulated in GR cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition, which was associated with decreased expression of vimentin, ZEB1, Slug, Snail, and nuclear factor-kappaB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemoresistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemoresistance toward the prevention of tumor progression and/or treatment of metastatic PC.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Asfar Sohail
authors.initials: AS
authors.lastname: Azmi
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000235:genetics; D051883:Receptor, Notch2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014162:Transfection; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D016328:NF-kappa B; C497764:NOTCH2 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051883:Receptor, Notch2; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine