Dataset Information

Selective inhibition of V600E-mutant BRAF gene induces apoptosis in thyroid carcinoma cell lines.

ABSTRACT:

Purpose

Papillary thyroid cancer (PTC) has a high incidence of BRAF^V600E mutation. The purpose of this study was to evaluate the potential relationship between thyroiditis and BRAF^V600E mutation status in patients with PTC. We investigated how a selective inhibitor of BRAF^V600E PLX4032 affects the proliferation and inflammatory cytokine levels of thyroid cancer.

Methods

Two thyroid cancer cell lines TPC1 and 8505C were treated with PLX4032, an analysis was done on cell growth, cell cycle, the degree of apoptosis, and levels of inflammatory cytokines. To identify the functional links of BRAF, we used the STRING database.

Results

Docking results illustrated PLX4032 blocked the kinase activity by exclusively binding on the serine/threonine kinase domain. STRING results indicated BRAF is functionally linked to mitogen-activated protein kinase. Both cell lines showed a dose-dependent reduction in growth rate but had a different half maximal inhibitory concentration value for PLX4032. The reaction to PLX4032 was more sensitive in the 8505C cells than in the TPC1 cells. PLX4032 induced a G2/M phase arrest in the TPC1 cells and G0/G1 in the 8505C cells. PLX4032 induced apoptosis only in the 8505C cells. With PLX4032, the TPC1 cells showed decreased levels of vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, chemokine (C-C motif) ligand 2/monocyte chemoattractant protein 1, whereas the 8505C cells showed significantly decreased levels of IL-8, serpin E1/plasminogen activator inhibitor-1, and matrix metalloproteinase (MMP)-3.

Conclusion

PLX4032 was cytotoxic in both TPC1 and 8505C cells and induced apoptosis. In the 8505C cells, inflammatory cytokines such as IL-8 and MMP-3 were down-regulated. These findings suggest the possibility that the BRAF^V600E mutation needs to target inflammatory signaling pathways in the treatment of thyroid cancer.

SUBMITTER: Park KS

PROVIDER: S-EPMC7943282 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Selective inhibition of V600E-mutant BRAF gene induces apoptosis in thyroid carcinoma cell lines.

Park Kyoung Sik KS Saindane Madhuri M Yang Eun Yeol EY Jin TongYi T Rallabandi Harikrishna Reddy HR Heil Alexander A Nam Sang Eun SE Yoo Young Bum YB Yang Jung-Hyun JH Kim Jong Bin JB Park Seo-Young SY Park Won Seo WS Youn Yeo-Kyu YK

Annals of surgical treatment and research 20210226 3

<h4>Purpose</h4>Papillary thyroid cancer (PTC) has a high incidence of BRAF<sup>V600E</sup> mutation. The purpose of this study was to evaluate the potential relationship between thyroiditis and BRAF<sup>V600E</sup> mutation status in patients with PTC. We investigated how a selective inhibitor of BRAF<sup>V600E</sup> PLX4032 affects the proliferation and inflammatory cytokine levels of thyroid cancer.<h4>Methods</h4>Two thyroid cancer cell lines TPC1 and 8505C were treated with PLX4032, an anal ...[more]

PMID: 33748026

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Project description:BackgroundThe MAPK/ERK signaling pathway is an essential regulator of numerous cell processes that are crucial for normal development as well as cancer progression. While much is known regarding MAPK/ERK signal conveyance from the cell membrane to the nucleus, the transcriptional and epigenetic mechanisms that govern gene expression downstream of MAPK signaling are not fully elucidated.ResultsThis study employed an integrated epigenome analysis approach to interrogate the effects of MAPK/ERK pathway inhibition on the global transcriptome, the active chromatin landscape, and protein-DNA interactions in 501mel melanoma cells. Treatment of these cells with the small-molecule MEK inhibitor AZD6244 induces hyperpigmentation, widespread gene expression changes including alteration of genes linked to pigmentation, and extensive epigenomic reprogramming of transcriptionally distinct regulatory regions associated with the active chromatin mark H3K27ac. Regulatory regions with differentially acetylated H3K27ac regions following AZD6244 treatment are enriched in transcription factor binding motifs of ETV/ETS and ATF family members as well as the lineage-determining factors MITF and SOX10. H3K27ac-dense enhancer clusters known as super-enhancers show similar transcription factor motif enrichment, and furthermore, these super-enhancers are associated with genes encoding MITF, SOX10, and ETV/ETS proteins. Along with genome-wide resetting of the active enhancer landscape, MEK inhibition also results in widespread SOX10 recruitment throughout the genome, including increased SOX10 binding density at H3K27ac-marked enhancers. Importantly, these MEK inhibitor-responsive enhancers marked by H3K27ac and occupied by SOX10 are located near melanocyte lineage-specific and pigmentation genes and overlap numerous human SNPs associated with pigmentation and melanoma phenotypes, highlighting the variants located within these regions for prioritization in future studies.ConclusionsThese results reveal the epigenetic reprogramming underlying the re-activation of melanocyte pigmentation and developmental transcriptional programs in 501mel cells in response to MEK inhibition and suggest extensive involvement of a MEK-SOX10 axis in the regulation of these processes. The dynamic chromatin changes identified here provide a rich genomic resource for further analyses of the molecular mechanisms governing the MAPK pathway in pigmentation- and melanocyte-associated diseases.

Dataset Information

Selective inhibition of V600E-mutant BRAF gene induces apoptosis in thyroid carcinoma cell lines.

Purpose

Methods

Results

Conclusion

Publications

Selective inhibition of V600E-mutant BRAF gene induces apoptosis in thyroid carcinoma cell lines.

Similar Datasets

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