Abstract
The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that Hh plays an important role in maintaining the cancer stem cell (CSCs) pool. Gemcitabine-resistant pancreatic cancer cells highly express some of the CSCs markers. However, the expression level of Hh members in gemcitabine-resistant pancreatic cancer cells remains unknown. The aim of this study was to verify the expression of HH members, such as Shh, Ptc, SMO and Gli-1 in gemcitabine-resistant PDAC cell lines, and to explore a new strategy to overcome chemoresistance in PDAC. Quantitative real-time RT-PCR (Q-PCR) and western blot were used to evaluate the relative expression level of HH members in SW1990, CFPAC-1 cells and gemcitabine-resistant SW1990, CFPAC-1 cells. The change of cancer stem cell markers and the expression level of HH members before and after cyclopamine treatment was evaluated using flow cytometry and Q-PCR, western blot, respectively. Cell apoptosis after cyclopamine treatment was measured by flow cytometry. CD44, CD133 and the expression level of HH members, including Shh, SMO, Gli-1, were found to be highly expressed in gemcitabine-resistant cells, which were significantly down-regulated by cyclopamine treatment. Flow cytometry analysis showed increased cell apoptosis after cyclopamine treatment. Gemcitabine-resistant pancreatic cancer cells highly express CSCs markers and some of the HH members, and inhibition of HH by cyclopamine is an effective method of reversing gemcitabine resistance in pancreatic cancer.
Highlights
Pancreatic cancer is among the most devastating of human malignancies
The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC)
Gemcitabine-resistant pancreatic cancer cells highly express some of the CSCs markers
Summary
Pancreatic cancer is among the most devastating of human malignancies. Despite recent improvements in surgical and chemotherapeutic approaches, pancreatic cancer continues to have a dismal prognosis, with an average overall median survival of 4–6 months. The clinical impact of gemcitabine remains modest [3] This limitation in conventional treatments is mainly due to the profound resistance of cancer cells to anti-cancer drugs, which can be inherent and/or acquired [4, 5]. Pancreatic cancer stem cells are highly tumorigenic and possess the abilities to self-renew and produce differentiated progeny. They are defined by the expression of the cell surface markers CD44, CD24 and ESA [9] and CD133. Are cancer stem cells more resistant to standard chemotherapy drugs, they employ different signalling pathways [12]. Activation of HH signalling is typically initiated by the binding of hedgehog ligands
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