Abstract
Pancreatic cancer is a highly aggressive malignancy, which is intrinsically resistant to current chemotherapies. Herein, we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggests that BDMC sensitizes gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC-1 and MiaPaCa-2 pancreatic cancer cells. Utilizing two-dimensional gel electrophoresis and mass spectrometry, we identify 13 essential proteins with significantly altered expressions in response to gemcitabine alone or combined with BDMC. Protein-protein interaction network analysis pinpoints glucose-regulated protein 78 (GRP78) as the key hub activated by BDMC. We then reveal that BDMC upregulates GRP78 and facilitates apoptosis through eIF2α/CHOP pathway. Moreover, DJ-1 and prohibitin, two identified markers of chemoresistance, are increased by gemcitabine in PANC-1 cells. This could be meaningfully reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In summary, these findings show that BDMC promotes apoptosis through a GRP78-dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.
Keywords:
apoptosis; bisdemethoxycurcumin; gemcitabine; pancreatic cancer; proteomics.
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Antimetabolites, Antineoplastic / pharmacology
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Cell Line, Tumor
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Curcumin / analogs & derivatives*
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Curcumin / pharmacology
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Diarylheptanoids
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2 / metabolism
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Gemcitabine
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondria / pathology
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Prohibitins
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Protein Deglycase DJ-1 / metabolism
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Protein Interaction Maps
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RNA Interference
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Repressor Proteins / metabolism
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Signal Transduction / drug effects
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Transcription Factor CHOP / metabolism
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Transfection
Substances
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Antimetabolites, Antineoplastic
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Antineoplastic Agents
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DDIT3 protein, human
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Diarylheptanoids
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2
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HSPA5 protein, human
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Heat-Shock Proteins
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Prohibitins
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Repressor Proteins
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Deoxycytidine
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Transcription Factor CHOP
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bisdemethoxycurcumin
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PARK7 protein, human
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Protein Deglycase DJ-1
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Curcumin
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Gemcitabine