Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer.
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Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. / Güngör, Cenap; Zander, Hilke; Harms-Effenberger, Katharina; Vashist, Yogesh; Kalinina, Tatiana; Izbicki, Jakob R.; Yekebas, Emre F.; Bockhorn, Maximilian.
In: CANCER RES, Vol. 71, No. 14, 14, 2011, p. 5009-5019.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer.
AU - Güngör, Cenap
AU - Zander, Hilke
AU - Harms-Effenberger, Katharina
AU - Vashist, Yogesh
AU - Kalinina, Tatiana
AU - Izbicki, Jakob R.
AU - Yekebas, Emre F.
AU - Bockhorn, Maximilian
PY - 2011
Y1 - 2011
N2 - The incidence of pancreatic ductal adenocarcinoma (PDAC) nearly equals its mortality rate, partly because most PDACs are intrinsically chemoresistant and thus largely untreatable. It was found recently that chemoresistant PDAC cells overexpress the Notch-2 receptor and have undergone epithelial-mesenchymal transition (EMT). In this study, we show that these two phenotypes are interrelated by expression of Midkine (MK), a heparin-binding growth factor that is widely overexpressed in chemoresistant PDAC. Gemcitabine, the front-line chemotherapy used in PDAC treatment, induced MK expression in a dose-dependent manner, and its RNAi-mediated depletion was associated with sensitization to gemcitabine treatment. We identified an interaction between the Notch-2 receptor and MK in PDAC cells. MK-Notch-2 interaction activated Notch signaling, induced EMT, upregulated NF-?B, and increased chemoresistance. Taken together, our findings define an important pathway of chemoresistance in PDAC and suggest novel strategies for its clinical attack.
AB - The incidence of pancreatic ductal adenocarcinoma (PDAC) nearly equals its mortality rate, partly because most PDACs are intrinsically chemoresistant and thus largely untreatable. It was found recently that chemoresistant PDAC cells overexpress the Notch-2 receptor and have undergone epithelial-mesenchymal transition (EMT). In this study, we show that these two phenotypes are interrelated by expression of Midkine (MK), a heparin-binding growth factor that is widely overexpressed in chemoresistant PDAC. Gemcitabine, the front-line chemotherapy used in PDAC treatment, induced MK expression in a dose-dependent manner, and its RNAi-mediated depletion was associated with sensitization to gemcitabine treatment. We identified an interaction between the Notch-2 receptor and MK in PDAC cells. MK-Notch-2 interaction activated Notch signaling, induced EMT, upregulated NF-?B, and increased chemoresistance. Taken together, our findings define an important pathway of chemoresistance in PDAC and suggest novel strategies for its clinical attack.
KW - Humans
KW - Cell Line, Tumor
KW - Signal Transduction
KW - Tumor Cells, Cultured
KW - Dose-Response Relationship, Drug
KW - RNA, Messenger/biosynthesis/genetics
KW - RNA Interference
KW - Drug Resistance, Neoplasm
KW - Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism/pathology
KW - Cytokines/biosynthesis/genetics
KW - Deoxycytidine/analogs & derivatives/pharmacology
KW - Epithelial-Mesenchymal Transition
KW - Fluorouracil/pharmacology
KW - Pancreatic Neoplasms/drug therapy/genetics/metabolism/pathology
KW - Receptor, Notch2/metabolism
KW - Humans
KW - Cell Line, Tumor
KW - Signal Transduction
KW - Tumor Cells, Cultured
KW - Dose-Response Relationship, Drug
KW - RNA, Messenger/biosynthesis/genetics
KW - RNA Interference
KW - Drug Resistance, Neoplasm
KW - Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism/pathology
KW - Cytokines/biosynthesis/genetics
KW - Deoxycytidine/analogs & derivatives/pharmacology
KW - Epithelial-Mesenchymal Transition
KW - Fluorouracil/pharmacology
KW - Pancreatic Neoplasms/drug therapy/genetics/metabolism/pathology
KW - Receptor, Notch2/metabolism
M3 - SCORING: Journal article
VL - 71
SP - 5009
EP - 5019
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 14
M1 - 14
ER -
