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Pancreatic ductal adenocarcinoma (PDAC) still remains an exceptional case among solid tumors, since its incidence nearly equals mortality rate. Despite formidable improvement of understanding the molecular mechanisms contributing to cancer progression and metastasis, no real progress has been done in catching cellular mechanisms governing chemotherapy-resistance in cancer cells, although almost all PDACs are intrinsically chemoresistant. It was recently shown that chemoresistant PDAC cells overexpress the Notch-2 receptor and acquire an epithelial-mesenchymal transitioned (EMT) phenotype. Cellular mechanisms that assist an EMT phenotype are not completely understood. However, the present study identified Midkine (MK) as frequently overexpressed in chemoresistant PDAC through gene-expression profiling and real-time PCR. We also found that MK expression is inducible by the chemotherapeutic gemcitabine in a dose-dependent manner in chemoresistant PDAC cells whereas no induction was observed in chemosensitive PDAC cells confirmed by real-time PCR. In addition, depletion of MK by RNAi correlated with decreased proliferation rates and more interestingly with a strong increase in sensitization towards gemcitabine. Main attraction is the identification of Notch-2 receptor as a new MK interactor in PDAC cells. Surprisingly, our results indicate that the MK-Notch-2 interaction activates Notch signaling in PDAC cells leading to induction of EMT, upregulation of NF-ΚB and increased chemoresistance. Combined, these results suggest that gemcitabine induced MK upregulation is strikingly involved in maintaining a drug resistance phenotype through binding and activation of Notch signaling. Thus, inhibition of this interaction may represent a novel strategy to attain the battle of chemoresistance in PDAC.