ABSTRACT
Glucose-regulated protein 78 (GRP78), a molecular chaperone, is overexpressed in patients suffering from obesity, fatty liver, hyperlipidemia and diabetes. GRP78, therefore, can be not only a biomarker to predict the progression and prognosis of obesity and metabolic diseases but also a potential therapeutic target for anti-obesity treatment. In this paper, GRP78 inhibitors targeting its ATPase domain have been reviewed. Small molecules and proteins that directly bind GRP78 have been described. Putative mechanisms of GRP78 in regulating lipid metabolism were also summarized so as to investigate the role of GRP78 in obesity and other related diseases and provide a theoretical basis for the development and design of anti-obesity drugs targeting GRP78.
Subject(s)
Endoplasmic Reticulum Chaperone BiP , Obesity , Humans , Endoplasmic Reticulum Chaperone BiP/antagonists & inhibitors , Obesity/drug therapy , Obesity/metabolismABSTRACT
BACKGROUND/AIM: HDAC6, a cytoplasmic localized deacetylase, is a positive regulator of cancer progression via modification of various substrates. We evaluated how the interaction between HDAC6 and glucose regulatory protein 78 (GRP78) affects the growth of cholangiocarcinoma (CCA). MATERIALS AND METHODS: The anti-tumor effects of ACY-1215, an HDAC6 specific inhibitor, in CCA cell lines were analyzed by cell viability assay, western blotting, flow cytometry, co-immunoprecipitation, and biotinylation assays. In vivo effects of ACY-1215 were evaluated in a xenograft model using CCA cell line TFK-1. RESULTS: ACY-1215 increased the acetyl-form of GRP78 by approximately 50% compared to control, which impaired the translocation of GRP78 to the plasma membrane by 50% through alteration of cellular proliferative signaling via PI3K/AKT. Furthermore, ACY-1215 suppressed tumor growth by 50% compared to vehicle control in a CCA xenograft model. CONCLUSION: Increase in GRP78 acetylation by HDAC6 inhibition suppressed GRP78 translocation to the cell surface, which inhibited proliferation and promoted apoptosis in CCA.
Subject(s)
Cell Proliferation/drug effects , Cholangiocarcinoma/drug therapy , Endoplasmic Reticulum Chaperone BiP/genetics , Histone Deacetylase 6/genetics , Animals , Cell Line, Tumor , Cell Membrane/drug effects , Cell Membrane/genetics , Cell Survival/drug effects , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Endoplasmic Reticulum Chaperone BiP/antagonists & inhibitors , Flow Cytometry , Humans , Hydroxamic Acids/pharmacology , Mice , Phosphatidylinositol 3-Kinases/genetics , Protein Transport/drug effects , Proto-Oncogene Proteins c-akt/genetics , Pyrimidines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Intermittent fasting (IF), as a dietary intervention for weight loss, takes effects primarily through increasing energy expenditure. However, whether inter-organ systems play a key role in IF remains unclear. Here, a novel hepatokine, pregnancy zone protein (PZP) is identified, which has significant induction during the refeeding stage of IF. Further, loss of function studies and protein therapeutic experiment in mice revealed that PZP promotes diet-induced thermogenesis through activating brown adipose tissue (BAT). Mechanistically, circulating PZP can bind to cell surface glucose-regulated protein of 78 kDa (GRP78) to promote uncoupling protein 1 (UCP1) expression via a p38 MAPK-ATF2 signaling pathway in BAT. These studies illuminate a systemic regulation in which the IF promotes BAT thermogenesis through the endocrinal system and provide a novel potential target for treating obesity and related disorders.
