Acquisition of Epithelial-Mesenchymal Transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of Notch signaling pathway

By Zhiwei Wang, Yiwei Li, D. Kong, Sanjeev Banerjee, Aamir Ahmad, Asfar S. Azmi, Shadan Ali, J. Abbruzzese, G. Gallick, Fazlul H. Sarkar. Cancer Research, 2009

630 citations recorded by the source corpus.

Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat, in part due to de novo and acquired chemo- and radio-resistance. 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 (CSC)”; however the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study demonstrates that Notch-2 and its ligand Jagged-1 are highly up-regulated in GR cells, which is consistent with the role of Notch signaling pathway in the acquisition of EMT and CSC 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 (MET), which was associated with decreased expression of vimentin, ZEB1, Slug, Snail and NF-κB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemo-resistance 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 chemo-resistance toward the prevention of tumor progression and/or treatment of metastatic PC.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/ebc03ea08c922b6f1faa37fefb24afecb6975ed5

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Citations in the corpus

Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis (2015, background): “NF-kB and Jagged can activate each other (188, 208), thereby forming a self-perpetuating loop that maintains both high levels of NF-kB and N-J signaling.”
Mathematical Modelling of Molecular Pathways Enabling Tumour Cell Invasion and Migration (2015, background): “The NICD GoF mutation, compared to the wild type, showed an increased probability for EMT as previously reported [126].”
The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer? (2010, background): “…to chemotherapeutics— such as gemcitabine, 5-Fu and cisplatin—in breast and pancreatic cancer cells (arumugam et al, 2009; Shah et al, 2007; Wang et al, 2009), and that zEB1 depletion sensitizes nSclc cells as well as head-and-neck cancer cells to the EgFr inhibitor erlotinib (Buck et…”