1. Academic Validation
  2. BRAF V600E protect from cell death via inhibition of the mitochondrial permeability transition in papillary and anaplastic thyroid cancers

BRAF V600E protect from cell death via inhibition of the mitochondrial permeability transition in papillary and anaplastic thyroid cancers

  • J Cell Mol Med. 2022 Jul;26(14):4048-4060. doi: 10.1111/jcmm.17443.
Yanyan Gao 1 2 Deyu Zhang 1 Fei Wang 1 Dejiu Zhang 1 Peifeng Li 1 Kun Wang 1
Affiliations

Affiliations

  • 1 Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.
  • 2 Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China.
Abstract

BRaf T1799A mutation is the most common genetic variation in thyroid Cancer, resulting in the production of BRaf V600E mutant protein reported to make cells resistant to Apoptosis. However, the mechanism by which BRaf V600E regulates cell death remains unknown. We constructed BRaf V600E overexpression and knockdown 8505C and BCPAP papillary and anaplastic thyroid Cancer cell to investigate regulatory mechanism of BRaf V600E in cell death induced by staurosporine (STS). Induced BRaf V600E expression attenuated STS-induced papillary and anaplastic thyroid Cancer death, while BRaf V600E knockdown aggravated it. TMRM and calcein-AM staining showed that opening of the mitochondrial permeability transition pore (mPTP) during STS-induced cell death could be significantly inhibited by BRaf V600E. Moreover, our study demonstrated that BRaf V600E constitutively activates mitochondrial ERK (mERK) to inhibit GSK-3-dependent CypD phosphorylation, thereby making BRaf V600E mutant tumour cells more resistant to mPTP opening. In the mitochondria of BRaf V600E mutant cells, there was an interaction between ERK1/2 and GSKa/ß, while upon BRaf V600E knockdown, interaction of GSKa/ß to ERK was decreased significantly. These results show that in thyroid Cancer, BRaf V600E regulates the mitochondrial permeability transition through the pERK-pGSK-CypD pathway to resist death, providing new intervention targets for BRaf V600E mutant tumours.

Keywords

BRAF V600E; anaplastic thyroid cancer cell; cell death; mitochondrial permeability transition; papillary thyroid cancer cell.

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