Abstract
BackgroundHuman pyruvate dehydrogenase phosphatase 1 (PDP1) plays an important physiological role in energy metabolism; however, its expression and function in human pancreatic adenocarcinoma (PDAC) remain unknown. This study aimed to investigate the expression pattern and mechanisms of action of PDP1 in human PDAC.MethodsThe expression pattern of PDP1 in PDAC was determined, and its correlation with patient survival was analyzed. Ectopic expression or knockdown of PDP1 was performed, and in vitro proliferation and migration, as well as in vivo tumor growth of PDAC, were measured. The mechanism was studied by biochemical approaches.ResultsPDP1 was overexpressed in human PDAC samples, and high expression of PDP1 correlated with poor overall and disease-free survival of PDAC patients. PDP1 promoted the proliferation, colony formation, and invasion of PDAC cells in vitro and facilitated orthotopic tumor growth in vivo. PDP1 accelerated intracellular ATP production, leading to sufficient energy to support rapid cancer progression. mTOR activation was responsible for the PDP1-induced tumor cell proliferation and invasion in PDAC. AMPK was downregulated by PDP1 overexpression, resulting in mTOR activation and cancer progression.ConclusionOur findings suggested that PDP1 could be a promising diagnostic and therapeutic target for anti-PDAC treatment.
Highlights
Pancreatic adenocarcinoma (PDAC), which accounts for 90% of pancreatic cancer cases, is among the top 10 life-threatening cancers, with a very high death rate and a survival rate of only approximately 5% [1]
Data retrieved from two published datasets of pancreatic adenocarcinoma (PDAC), GSE15471 and GSE28735, revealed that pyruvate dehydrogenase phosphatase 1 (PDP1) was overexpressed in human PDAC tissues compared with the nonmalignant normal pancreatic tissues (Fig. 1a, b)
We found that the expression of PDP1 predicted poor overall survival and disease-free survival of the PDAC patients (p = 0.0285 and p = 0.0380, respectively), which indicates that PDP1 may be a poor prognostic factor in PDAC (Fig. 1d, e)
Summary
Pancreatic adenocarcinoma (PDAC), which accounts for 90% of pancreatic cancer cases, is among the top 10 life-threatening cancers, with a very high death rate and a survival rate of only approximately 5% [1]. The human PDP1 gene encodes pyruvate dehydrogenase phosphatase (PDP) 1, one of the two PDP isoforms in mammalian cells [8]. Mutation of PDP1 in some patients may cause PDC deficiency, a genetic disorder characterized by neurodegeneration and abnormal metabolism [11]. The expression of PDP1 in muscle cells of obese and diabetic subjects was reduced and could be reversed by endurance training [14, 15]. The expression pattern and function of PDP1 in PDAC remain unclear. Human pyruvate dehydrogenase phosphatase 1 (PDP1) plays an important physiological role in energy metabolism; its expression and function in human pancreatic adenocarcinoma (PDAC) remain unknown. This study aimed to investigate the expression pattern and mechanisms of action of PDP1 in human PDAC
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