Bisdemethoxycurcumin exerts pro-apoptotic effects in human pancreatic adenocarcinoma cells through mitochondrial dysfunction and a GRP78-dependent pathway
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Haopeng Yang1,2, Shengjun Fan1,2, Yu An1,2, Xin Wang2, Yan Pan1,2, Yilixiati Xiaokaiti1,2, Jianhui Duan1,2, Xin Li1,2, Lu Tie1,2, Min Ye1,3, Xuejun Li1,2
1State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
2Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China
3Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
Xuejun Li, email: firstname.lastname@example.org
Keywords: bisdemethoxycurcumin, gemcitabine, pancreatic cancer, apoptosis, proteomics
Received: July 02, 2016 Accepted: October 14, 2016 Published: November 10, 2016
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.
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