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.

Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy

“…GRP78 (BiP) is a 78-kDa protein chaperone [26,27] that has been proven to prevent the cell death caused by disturbance of endoplasmic reticulum (ER) homeostasis [28] and to mediate essential components of ER stress-induced apoptosis [31][32][33]. Fluorescent labeling and immunofluorescence staining indicated that TTR efficiently crossed cell membrane and nuclear membrane; the localization of TTR and GRP78 partially overlapped in and around the nuclei.…”

Curcumin analogs: Their roles in pancreatic cancer growth and metastasis

“…It was also associated with elevated poly ADP‐ribose polymerase (PARP) and cleaved caspase‐3. Moreover, BDMC was found to greatly enhance the antitumor effects of GEM in both cell lines …”

“…Another study reported that the BDMC-gemcitabine (GEM) combination induced the greatest mitochondrial dysfunction and apoptosis in PANC-1 and MIA PaCa-2 cells. 23 Apoptosis was observed in greater than 60% of the cell lines treated with BDMC-GEM. It was also associated with elevated poly ADPribose polymerase (PARP) and cleaved caspase-3.…”

“…Our study also found that the curcuminoid mix led to the lowest cell viability in PANC‐1 cells, followed again by curcumin, DMC, and BDMC. Another study reported that the BDMC‐gemcitabine (GEM) combination induced the greatest mitochondrial dysfunction and apoptosis in PANC‐1 and MIA PaCa‐2 cells . Apoptosis was observed in greater than 60% of the cell lines treated with BDMC‐GEM.…”

Modification of radiosensitivity by Curcumin in human pancreatic cancer cell lines

“…The influence of curcumin on multiple cellular pathways like NFkB-, PI3-kinase-or p53-activity leading to inhibition of proliferation and induction of apoptosis was shown in preclinical models of different tumor entities, including pancreatic cancer [13][14][15] . In addition, impact on formation of reactive oxygen species, regulating RNAs, mitochondrial function, cell membrane and epigenetic changes were described using Curcumin in tumor cell treatment [16][17][18][19][20] . Some in vitro studies demonstrated radiosensitization by Curcumin, e.g.…”