4.6 Article Proceedings Paper

A novel heat shock protein inhibitor KU757 with efficacy in lenvatinib-resistant follicular thyroid cancer cells overcomes up-regulated glycolysis in drug-resistant cells in vitro

Journal

SURGERY
Volume 169, Issue 1, Pages 34-42

Publisher

MOSBY-ELSEVIER
DOI: 10.1016/j.surg.2020.06.009

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Funding

  1. National Institutes of Health [T32 CA009672, R01 CA173292, R01 CA216919, 3U01 CA120458]
  2. Coller Surgical Society Research Fellowship
  3. University of Michigan Comprehensive Cancer Center [P30-CA-046592]
  4. University of Michigan Department of Surgery

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The study reveals that lenvatinib-resistant thyroid cancer cells exhibit increased dependency on glycolysis, which can be effectively treated by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids with KU757.
Background: Patients with advanced differentiated thyroid cancer develop resistance to lenvatinib treatment from metabolic dysregulation. Heat shock protein 90 is a molecular chaperone that plays an important role in glycolysis and metabolic pathway regulation. We hypothesize that lenvatinib-resistant differentiated thyroid cancer cells will have an increased dependency on glycolysis and that a novel Cterminal heat shock protein 90 inhibitor (KU757) can effectively treat lenvatinib-resistant cells by targeting glycolysis. Methods: Inhibitory concentration 50 values of thyroid cancer cells were determined by CellTiter-Glo assay (Promega Corp, Madison, WI). Glycolysis was measured through Seahorse experiments. Reverse transcription-polymerase chain reaction and Western blot evaluated glycolytic pathway genes/proteins. Exosomes were isolated/validated by nanoparticle tracking analysis and Western blot. Differentially expressed long non-coding ribonucleic acids in exosomes and cells were evaluated using quantitative polymerase chain reaction. Results: Extracellular acidification rate demonstrated >2-fold upregulation of glycolysis in lenvatinibresistant cells versus parent cells and was downregulated after KU757 treatment. Lenvatinib-resistant cells showed increased expression of the glycolytic genes lactic acid dehydrogenase, pyruvate kinase M1/2, and hexokinase 2. KU757 treatment resulted in downregulation of these genes and proteins. Several long non-coding ribonucleic acids associated with glycolysis were significantly upregulated in WRO-lenvatiniberesistant cells and exosomes and downregulated after KU757 treatment. Conclusion: Lenvatinib resistance leads to increased glycolysis, and KU757 effectively treats lenvatinibresistant cells and overcomes this increased glycolysis by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids. (C) 2020 Elsevier Inc. All rights reserved.

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