PTPN11 Knockdown Prevents Changes in the Expression of Genes Controlling Cell Cycle, Chemotherapy Resistance, and Oncogene-Induced Senescence in Human Thyroid Cells Overexpressing BRAF V600E Oncogenic Protein

• Published in: Biochemistry (Moscow) 2020, Vol.85 (1), p.108-118
• Main Authors: Putlyaeva, L. V., Demin, D. E., Uvarova, A. N., Zinevich, L. S., Prokofjeva, M. M., Gazizova, G. R., Shagimardanova, E. I., Schwartz, A. M.
• Format: Article
• Language: English
• Subjects: Aging; Analysis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cell Cycle; Cell differentiation; Cell Line; Cell proliferation; Cell survival; Cellular Senescence; Chemoresistance; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm - physiology; Emergence; Epithelium; External stimuli; Extracellular signal-regulated kinase; Gene expression; Gene Knockdown Techniques; Gene mutations; Genes; Genetic aspects; Humans; Influence; Inhibitors; Kinases; Life Sciences; MAP kinase; Microbiology; Mutation; Oncogenes; Prevention; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - physiology; Protein-tyrosine-phosphatase; Proto-Oncogene Proteins B-raf - metabolism; Senescence; SHP-2 protein; Signal transduction; Signaling; siRNA; Thyroid; Thyroid cancer; Thyroid Epithelial Cells - cytology; Thyroid Epithelial Cells - metabolism; Thyroid gland; Thyroid Gland - cytology; Thyroid Gland - metabolism; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transcription activation; Tumors; Tyrosine; Vemurafenib - therapeutic use
• ISSN: 0006-2979; 1608-3040
• DOI: 10.1134/S0006297920010101

The MAPK (RAS/BRAF/MEK/ERK) signaling pathway is a kinase cascade involved in the regulation of cell proliferation, differentiation, and survival in response to external stimuli. The V600E mutation in the BRAF gene has been detected in various tumors, resulting in a 500-fold increase in BRAF kinase activity. However, monotherapy with selective BRAF V600E inhibitors often leads to reactivation of MAPK signaling cascade and emergence of drug resistance. Therefore, new targets are being developed for the inhibition of components of the aberrantly activated cascade. It was recently discovered that resistance to BRAF V600E inhibitors may be associated with the activity of the tyrosine phosphatase SHP-2 encoded by the PTPN11 gene. In this paper, we analyzed transcriptional effects of PTPN11 gene knockdown and selective suppression of BRAF V600E in a model of thyroid follicular epithelium. We found that the siRNA-mediated knockdown of PTPN11 after vemurafenib treatment prevented an increase in the expression CCNA1 and NOTCH4 genes involved in the formation of drug resistance of tumors. On the other hand, downregulation of PTPN11 expression blocked the transcriptional activation of genes ( p21, pl5, pl6, RBI , and IGFBP7 ) involved in cell cycle regulation and oncogene-induced senescence in response to BRAF V600E expression. Therefore, it can be assumed that SHP-2 participates not only in emergence of drug resistance in cancer cells, but also in oncogene-induced cell senescence.