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

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Listed:
  • Ying Yang

    (University of California)

  • Mari B. Ishak Gabra

    (University of California)

  • Eric A. Hanse

    (University of California)

  • Xazmin H. Lowman

    (University of California)

  • Thai Q. Tran

    (University of California)

  • Haiqing Li

    (City of Hope
    City of Hope)

  • Neta Milman

    (The Technion-Israel Institute of Technology)

  • Juan Liu

    (Duke University School of Medicine)

  • Michael A. Reid

    (Duke University School of Medicine)

  • Jason W. Locasale

    (Duke University School of Medicine)

  • Ziv Gil

    (The Technion-Israel Institute of Technology)

  • Mei Kong

    (University of California)

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.

Suggested Citation

  • Ying Yang & Mari B. Ishak Gabra & Eric A. Hanse & Xazmin H. Lowman & Thai Q. Tran & Haiqing Li & Neta Milman & Juan Liu & Michael A. Reid & Jason W. Locasale & Ziv Gil & Mei Kong, 2019. "MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08759-0
    DOI: 10.1038/s41467-019-08759-0
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    Cited by:

    1. Ying Yang & Michael A. Reid & Eric A. Hanse & Haiqing Li & Yuanding Li & Bryan I. Ruiz & Qi Fan & Mei Kong, 2023. "SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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