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. 2020 Aug 6:10:95.
doi: 10.1186/s13578-020-00457-5. eCollection 2020.

Overexpression of pyruvate dehydrogenase phosphatase 1 promotes the progression of pancreatic adenocarcinoma by regulating energy-related AMPK/mTOR signaling

Ye Li #  1   2 , Jia Shen #  3 , Chien-Shan Cheng  1   2 , HuiFeng Gao  1   2 , Jiangang Zhao  4 , Lianyu Chen  1   2
Affiliations

Overexpression of pyruvate dehydrogenase phosphatase 1 promotes the progression of pancreatic adenocarcinoma by regulating energy-related AMPK/mTOR signaling

Ye Li et al. Cell Biosci. .

Abstract

Background: Human 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.

Methods: The 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.

Results: PDP1 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.

Conclusion: Our findings suggested that PDP1 could be a promising diagnostic and therapeutic target for anti-PDAC treatment.

Keywords: AMPK; ATP; Pancreatic adenocarcinoma; Pyruvate dehydrogenase phosphatase 1; mTOR.

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Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
PDP1 was overexpressed in PDAC. Data were retrieved from the GEO database, and PDP1 was found to be overexpressed in PDAC tissues compared with normal pancreatic tissues in (a) GSE15471 and (b) GSE28735. c Immunohistochemical staining of PDP1 was retrieved from the Human Protein Atlas, which suggested that PDP1 protein expression was upregulated in PDAC tissues. Survival of PDAC patients was retrieved from TGCA database, and patients with PDP1 expression above the median level had poor (d) overall survival and (e) disease-free survival. f Surviving PDAC patients had lower expression of PDP1 than the censored patients
Fig. 2
Fig. 2
PDP1 regulated PDAC cell proliferation and migration in vitro. a Transfection of the PDP1 ORF clone or shRNA regulated endogenous expression of PDP1 in PDAC cells. b Overexpression of PDP1 promoted PDAC cell proliferation, while PDP1 suppressed PDAC cell proliferation. c Overexpression of PDP1 promoted colony formation of PDAC cells, while PDP1 suppressed PDAC cell colony number. d Overexpression of PDP1 promoted PDAC cell migration, while PDP1 suppressed PDAC cell migration. ***p < 0.001
Fig. 3
Fig. 3
PDP1 overexpression promoted PDAC growth in vivo. a PDP1 overexpression significantly increased the luciferase signal in the orthotopic tumors of PDAC in mice; b PDP1 overexpression increased the tumor size of the orthotopic PDAC model; c H&E staining suggested that more cells were undergoing mitotic proliferation in the PDP1-overexpressing tumors than the control tumors; d PDP1-overexpressing tumors expressed a higher level of PCNA than the control tumors. ***p < 0.001
Fig. 4
Fig. 4
PDP1 induced PDAC cell proliferation and migration by inducing intracellular ATP. a PDP1 overexpression induced intracellular ATP content, while its knockdown reduced ATP levels. Supplementation of an alternative substrate of ATP production, acetate, restored cell proliferation (b), colony formation (c) and migration of PDP1 knockdown PDAC cells (d). ***p < 0.001
Fig. 5
Fig. 5
mTOR was responsible for PDP1-mediated PDAC cell proliferation and migration. a The phosphorylation of mTOR in PDAC cells, representing its activity, was measured by immunoblotting. PDP1 overexpression activated mTOR signaling, while its knockdown suppressed mTOR phosphorylation. b Transfection of constitutively activated mTORC reactivated mTOR signaling in PDP1 knockdown PDAC cells. mTORC represents a plasmid encoding a mutated mTOR with a change from arginine 2505 to proline, which leads to constitutive activation of mTOR regardless of intracellular signaling. Reactivation of mTOR restored cell proliferation (c), colony formation (d), and migration of PDP1 knockdown PDAC cells (e). ***p < 0.001
Fig. 6
Fig. 6
AMPK inactivation was responsible for PDP1-mediated PDAC cell proliferation and migration. a PDP1 overexpression suppressed AMPK signaling, while its knockdown induced activation via phosphorylation. b The presence of compound C (20 mM) inactivated AMPK signaling in PDP1 knockdown PDAC cells, which in turn reactivated mTOR signaling. Reactivation of mTOR restored cell proliferation (c), colony formation (d), and migration of PDP1 knockdown PDAC cells (e). f AMP was supplemented in the PDP1-overexpressing cells to adjust the intracellular AMP:ATP ratio. Increased AMP:ATP ratio in the PDP-overexpressing cells resulted in the restoration of AMPK activity but mTOR repression. ***p < 0.001
Fig. 7
Fig. 7
Schematic regulation of PDP1 in PDAC. Overexpression of PDP1 may activate PDH, which in turn accelerates the TCA cycle, which provides reducing equivalents in the form of NADH, FADH2, etc. for the ATP production by oxidative phosphorylation. The abundance of cellular ATP inhibits AMPK activation, restoring the mTOR signaling that can promote proliferation and invasion of PDAC cells
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