Format

Send to

Choose Destination
Oncotarget. 2016 Dec 13;7(50):83641-83656. doi: 10.18632/oncotarget.13272.

Bisdemethoxycurcumin exerts pro-apoptotic effects in human pancreatic adenocarcinoma cells through mitochondrial dysfunction and a GRP78-dependent pathway.

Yang H1,2, Fan S1,2, An Y1,2, Wang X2, Pan Y1,2, Xiaokaiti Y1,2, Duan J1,2, Li X1,2, Tie L1,2, Ye M1,3, Li X1,2.

Author information

1
State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
2
Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
3
Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

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

PMID:
27845899
PMCID:
PMC5347794
DOI:
10.18632/oncotarget.13272
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center