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The prognosis of pancreatic cancer remains disappointing due to a high intrinsicresistance against chemotherapeutic agents. Standard gemcitabine therapies haveimproved overall survival only marginally and recently, inhibition of the proteasomeby the boronic acid derivative bortezomib has been introduced as a novel therapeuticstrategy for solid and hematological malignancies including pancreatic cancer.The mucus-producing pancreatic cancer cell line Capan-1 was cultured under standardconditions and treated with different concentrations of gemcitabine or bortezomib.Mucus production was suppressed by siRNA-mediated silencing of apomucin genes.Cell proliferation was determined by 3H-thymidine incorporation and apoptosiswas quantified after propidium iodide staining by flow cytometry. Apoptotic celldeath was confirmed by TUNEL staining, determination of mitochondrial transmembranepotential and assessment of caspase 3/7 activity. NFκB-activity was determinedby EMSA. The unfolded protein response (UPR) was further investigated by PCR,Western blotting and caspase 12 activity assays. Silencing of MUC4 significantlyreduced expression of mucins for up to 5 days after transfection. While nativecells showed an increased sensitivity to bortezomib treatment, silenced cellswere more sensitive to gemcitabine treatment. Bortezomib induces mitochondrialdamage in native cells and also activates the UPR by splicing of Xbp-1 and inductionof CHOP, which is significantly reduced by silencing of MUC4. Our data suggestthat mucinous pancreatic cancers are more sensitive towards proteasome inhibitionby bortezomib and that alternative pathways of apoptosis are involved in celldeath induction, while tumor cells with a low secretory activity show a betterresponse to gemcitabine.

Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells