title: Bisdemethoxycurcumin exerts pro-apoptotic effects in human pancreatic adenocarcinoma cells through mitochondrial dysfunction and a GRP78-dependent pathway.
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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Haopeng
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.affiliation: Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Yilixiati
authors.initials: Y
authors.lastname: Xiaokaiti
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Tie
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.|Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D036381:Diarylheptanoids; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000091402:Prohibitins; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism; D060066:Protein Interaction Maps; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D036381:Diarylheptanoids; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D000091402:Prohibitins; D012097:Repressor Proteins; D003841:Deoxycytidine; D051742:Transcription Factor CHOP; C034786:bisdemethoxycurcumin; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D003474:Curcumin; D000093542:Gemcitabine
keywords: apoptosis; bisdemethoxycurcumin; gemcitabine; pancreatic cancer; proteomics