BRAF V600E /p-ERK/p-DRP1(Ser616) Promotes Tumor Progression and Reprogramming of Glucose Metabolism in Papillary Thyroid Cancer

作者：Shishuai Wen, Yi-Jun Wu, Jiayang Wang, Zhaoxian Ni, Shuai Dong, Xiaojun Xie, Yuting Wang, Yu Wang, Naisi Huang, Qinghai Ji, Ben Ma, Ning Qu · 发表于：Thyroid · 年份：2024 · DOI：10.1089/thy.2023.0700 · 被引用次数：16 · 研究领域：Thyroid Cancer Diagnosis and Treatment、Cancer, Hypoxia, and Metabolism、S100 Proteins and Annexins

Background: Papillary thyroid cancer (PTC) with the BRAF V600E mutation is associated with a poorer prognosis. BRAF inhibitors may demonstrate limited efficacy due to emerging drug resistance. The Warburg effect may have cancer therapeutic implications. It is not known if the BRAF V600E mutation is associated with altered glucose metabolism in PTC. Methods: This study examined the effect of BRAF V600E and dynamin-related protein 1 (DRP1) on various cellular processes in PTC cells, including cell proliferation, migration, invasion, mitochondrial fission, glucose metabolism, reactive oxygen species (ROS) generation, and apoptosis. We used RT-qPCR to assess the expression of key glycolytic enzymes in thyroid cancer tissues. Additionally, the regulatory interaction between BRAF V600E and DRP1 was investigated through Western blot and immunohistochemical staining. We further evaluated the impact of DRP1 in PTC and the inhibitory effects of dabrafenib and 2-deoxy- d -glucose (2-DG) in vitro and in vivo . Results: We found that the BRAF V600E mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAF V600E /p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. First, the BRAF V600E /p-ERK/p-DRP1(Ser616) signaling pathway enhances cell proliferation by upregulating hexokinase 2 expression and thereby increasing aerobic glycolysis. Second, it inhibits apoptosis by promoting mitochondrial fis...