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Nat Commun. 2019 Feb 18;10(1):809. doi: 10.1038/s41467-019-08759-0.

MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1.

Author information

1
Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, 92697, USA.
2
Center for Informatics, City of Hope, Duarte, CA, 91010, USA.
3
Department of Computational & Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA.
4
Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Healthcare Campus, The Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
5
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27708, USA.
6
Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, 92697, USA. meik1@uci.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.

PMID:
30778058
PMCID:
PMC6379428
DOI:
10.1038/s41467-019-08759-0
[Indexed for MEDLINE]
Free PMC Article

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