Otręba Michał, Sjölander Johanna Johansson, Grøtli Morten, Sunnerhagen Per
Department of Drug Technology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Jednosci 8, 41-200 Sosnowiec, Poland.
Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden.
Life (Basel). 2021 Mar 31;11(4):297. doi: 10.3390/life11040297.
Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative stress. To investigate the generality of these findings, we now study the effect of INR119 in human cells under similar conditions. Cells of the established breast cancer line MCF-7 were exposed to HO or phenothiazines, alone or combined with INR119. In line with the previous results in fission yeast, the phosphorylation of the MAPKs ERK and p38 increased substantially more with the combination treatment than by HO or phenothiazines, whereas INR119 alone did not affect phosphorylation. We also measured the mRNA levels of and , known to be affected by ERK and p38 activity. Similarly, the combination of INR119 and phenothiazines increased both mRNAs to higher levels than for phenothiazines alone. In conclusion, the mechanism of action of INR119 on its target protein kinase may be conserved between yeast and humans.
小分子常被用于抑制蛋白激酶，但能够增强激酶活性的调节剂却很罕见。我们之前已经表明，设计为MEK1/2抑制剂的小分子INR119在氧化应激条件下会增强其裂殖酵母同源物Wis1的活性。为了研究这些发现的普遍性，我们现在在类似条件下研究INR119在人类细胞中的作用。已建立的乳腺癌细胞系MCF-7的细胞单独或与INR119联合暴露于HO或吩噻嗪。与之前在裂殖酵母中的结果一致，联合处理时MAPKs ERK和p38的磷酸化增加幅度比单独使用HO或吩噻嗪时显著更大，而单独的INR119不影响磷酸化。我们还测量了已知受ERK和p38活性影响的 和 的mRNA水平。同样，INR119和吩噻嗪的联合使两种mRNA水平都比单独使用吩噻嗪时更高。总之，INR119对其靶蛋白激酶的作用机制在酵母和人类之间可能是保守的。
