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Mol Cell. 2017 Aug 17;67(4):685-701.e6. doi: 10.1016/j.molcel.2017.07.014. Epub 2017 Aug 10.

Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Singapore Institute of Clinical Sciences, Agency for Science Technology and Research (A(∗)STAR), Brenner Center for Molecular Medicine, Singapore 117609, Singapore.
3
Department of Surgery, Yale University School of Medicine, New Haven, CT 06510, USA.
4
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
5
Department of Internal Medicine and Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA.
6
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: narendra.wajapeyee@yale.edu.

Abstract

Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1-mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK). In turn, AMPK activates FOXO3A and its transcriptional target, PUMA, which induces anoikis to suppress PDAC tumor growth and metastasis. Pharmacological or genetic activation of AMPK, similar to PON2 inhibition, blocks PDAC tumor growth. Collectively, our results identify PON2 as a new modulator of glucose transport that regulates a pharmacologically tractable pathway necessary for PDAC tumor growth and metastasis.

KEYWORDS:

GLUT1; PON2; anoikis; glucose; metabolism; pancreatic cancer

PMID:
28803777
PMCID:
PMC5567863
DOI:
10.1016/j.molcel.2017.07.014
[Indexed for MEDLINE]
Free PMC Article

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