The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.
The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.
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DOI：
10.1016/j.cellsig.2020.109605
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发表时间：
2020-07
影响因子：
4.8
通讯作者：
Edelstein CL
中科院分区：
文献类型：
--
作者：
Brown CN;Atwood DJ;Pokhrel D;Ravichandran K;Holditch SJ;Saxena S;Miyazaki M;Nemenoff R;Weiser-Evans MCM;Ljubanovic DG;Joy MS;Edelstein CL
在一个4周的临床相关模型中，小鼠皮下注射小鼠非小细胞肺癌(NSCLC)细胞，该细胞携带激活的Kirsten大鼠肉瘤病毒癌基因同源(KRAS)G12V突变。MEK1/2抑制剂U0126和曲美替尼可有效抑制pERK1/2在肾脏和肿瘤中的表达。U0126可显著改善AKI小鼠的肾功能、急性肾小管坏死(ATN)和肾小管上皮细胞凋亡。被U0126显著下调的基因有热休克蛋白1、细胞周期蛋白依赖蛋白4和层翅蛋白(14-3-3σ)。U0126可显著降低肿瘤重量和体积，显著提高顺铂的化疗效果。曲美替尼是一种MEK1/2抑制剂，已被FDA批准用于癌症的治疗，它没有对AKI或更严重的AKI产生功能保护，但比顺铂更显著地抑制肿瘤生长。顺铂或MEK1/2抑制剂治疗的小鼠较小的肿瘤与微管相关蛋白1A/1B轻链3B(LC3-II)、p62、裂解caspase-3、颗粒酶B或程序性死亡配体1(PD-L1)的变化无关。总之，尽管U0126和曲美替尼都抑制ERK，但只有U0126对AKI有保护作用，这表明U0126对AKI的保护是由于一种独立于ERK抑制的非靶点效应。U0126降低AKI的作用可能是通过抑制热休克蛋白1、CDK4或层翅蛋白(14-3-3σ)实现的。曲美替尼在减少肿瘤生长方面比顺铂更有效，但与顺铂不同，曲美替尼不会导致AKI。
In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS)G12V mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI. Genes that were significantly decreased by U0126 were heat shock protein 1, cyclin-dependent kinase 4 (CDK4) and stratifin (14–3–3σ). U0126 resulted in a significant decrease in tumor weight and volume and significantly increased the chemotherapeutic effect of cisplatin. Trametinib, a MEK1/2 inhibitor that is FDA-approved for the treatment of cancer, did not result in functional protection against AKI or worse AKI, but dramatically decreased tumor growth more than cisplatin. Smaller tumors in cisplatin or MEK1/2 inhibitor-treated mice were not related to changes in microtubule-associated proteins 1A/1B light chain 3B (LC3-II), p62, cleaved caspase-3, granzyme B, or programmed death-ligand 1 (PD-L1). In summary, despite ERK inhibition by both U0126 and trametinib, only U0126 protected against AKI suggesting that the protection against AKI by U0126 was due to an off-target effect independent of ERK inhibition. The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14–3–3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI.
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