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

Autor:	Wen SS; Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Wu YJ; Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China., Wang JY; Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China., Ni ZX; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Dong S; Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China., Xie XJ; Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China., Wang YT; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Wang Y; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Huang NS; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Ji QH; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Ma B; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China., Qu N; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Jazyk:	angličtina
Zdroj:	Thyroid : official journal of the American Thyroid Association [Thyroid] 2024 Oct; Vol. 34 (10), pp. 1246-1259. Date of Electronic Publication: 2024 Sep 27.
DOI:	10.1089/thy.2023.0700
Abstrakt:	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 fission and reducing ROS levels. Moreover, we demonstrated that the combination therapy of 2-DG and dabrafenib markedly impedes the progression of BRAF V600E -positive PTC. Conclusion: The BRAF V600E /p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAF V600E -positive PTC. Our findings suggest that a combined therapeutic approach using 2-DG and dabrafenib has the potential to improve the outcome of PTC patients with BRAF V600E .
Databáze:	MEDLINE
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