HER2 EKSPRESYONU OLAN MEME KANSERİ HÜCRELERİNDE ÖKARYOTİK ELONGASYON FAKTÖR-2 KİNAZ (eEF2K) AKTİVASYONUNUN ROLÜ

Abstract

Continuous activation of HER2 leads to the deregulation of various biological responses such as cell proliferation, survival, and migration, and tumor growth. eEF2K is a protein kinase involved in the regulation of protein synthesis. It is known that, in some cancer cells, with the increase of eEF2K activity, the cells develop adaptation to stress conditions and drug resistance. The expression level and activity of eEF2K in HER2-expressing cancer cells is not yet known. As a result of the in silico analyzes performed in line with this purpose, it was determined that gene expressions of HER2-related signaling pathway were correlated with eEF2K gene expression and eEF2K was more regulated in HER2+ breast cancer compared to TNBC (triple negative breast cancer) breast cancer. the inhibitory effect of trastuzumab on the PI3K/Akt/mTOR signaling pathway was demonstrated and its relationship with eEF2K/eEF2 protein activities in five HER2-expressing cell lines. It was determined that the strongest inhibitory effect of trastuzumab in the signal cascade was on Akt activation. In BT-474, MDA-MB-361, MDA-MB-453 and UACC-893 cells treated with drugs, it was shown that the activation of eEF2K decreased after 6 hours, but increased at the end of 48 hours and decreased proliferation with the increase in eEF2 phosphorylation. Changes in eEF2K activity were found to be consistent with the effect of trastuzumab on S6K protein activation. Accordingly, the effect of suppression of AKT and S6K activities on eEF2-mediated cell proliferation in HER2-expressing breast cancer was demonstrated for the first time. According to cell proliferation analysis, a stronger suppression of proliferation in BT-474 and SKBR-3 cells was noted. In addition to these results, the expression of AMPK, which is the activator of eEF2K, was also found to be statistically significantly decreased in BT-474 and SKBR-3 cells. As a result, it was concluded that PI3K/Akt/mTor signaling pathway has a regulatory effect on eEF2K activity in HER2-expressing breast cancer cell lines with, and eEF2K may be an important therapeutic target in HER2-expressing breast cancer.