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BRAFV600E/p-ERK/p-DRP1(Ser616) Promotes Tumor Progression and Reprogramming of Glucose Metabolism in Papillary Thyroid Cancer

  • 0Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.
Thyroid : Official Journal of the American Thyroid Association +

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August 20, 2024

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August 20, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

The BRAF<sup>V600E</sup> mutation in papillary thyroid cancer drives aerobic glycolysis and progression via the BRAF/ERK/DRP1 pathway. Combination therapy with 2-deoxy-D-glucose (2-DG) and dabrafenib shows promise for treating BRAF<sup>V600E</sup>-positive PTC.

Area Of Science

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background

  • Papillary thyroid cancer (PTC) with BRAF<sup>V600E</sup> mutation has a poor prognosis, with limited BRAF inhibitor efficacy due to resistance.
  • The Warburg effect's role in cancer and its association with BRAF<sup>V600E</sup> in PTC remain unclear.

Purpose Of The Study

  • To investigate the impact of BRAF<sup>V600E</sup> and dynamin-related protein 1 (DRP1) on PTC cellular processes, including glucose metabolism.
  • To elucidate the BRAF<sup>V600E</sup>/DRP1 regulatory interaction and its role in PTC progression.
  • To evaluate the efficacy of combined 2-deoxy-D-glucose (2-DG) and dabrafenib therapy.

Main Methods

  • RT-qPCR to analyze glycolytic enzyme expression in thyroid cancer tissues.
  • Western blot and immunohistochemistry to study BRAF<sup>V600E</sup> and DRP1 interaction.
  • In vitro and in vivo evaluation of BRAF<sup>V600E</sup>, DRP1, and therapeutic interventions.

Main Results

  • BRAF<sup>V600E</sup> mutation significantly increases aerobic glycolysis and decreases oxidative phosphorylation in PTC.
  • The BRAF<sup>V600E</sup>/p-ERK/p-DRP1(Ser616) pathway upregulates hexokinase 2, enhances cell proliferation, promotes mitochondrial fission, and reduces ROS levels, inhibiting apoptosis.
  • Combined 2-DG and dabrafenib therapy effectively inhibits the progression of BRAF<sup>V600E</sup>-positive PTC.

Conclusions

  • The BRAF<sup>V600E</sup>/p-ERK/p-DRP1(Ser616) pathway is crucial for glucose metabolism reprogramming and aggressive progression in BRAF<sup>V600E</sup>-positive PTC.
  • Targeting this pathway with combined 2-DG and dabrafenib offers a potential therapeutic strategy to improve outcomes for PTC patients with BRAF<sup>V600E</sup> mutations.

Keywords:

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