Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany.
Int J Mol Sci. 2023 Sep 4;24(17):13661. doi: 10.3390/ijms241713661.
The three major MAP-kinase (MAPK) pathways, ERK1/2, p38 and JNK/SAPK, are upstream regulators of the nuclear "hormone" receptor superfamily (NHRSF), with a prime example given by the estrogen receptor in breast cancer. These ligand-activated transcription factors exert non-genomic and genomic functions, where they are either post-translationally modified by phosphorylation or directly interact with components of the MAPK pathways, events that govern their transcriptional activity towards target genes involved in cell differentiation, proliferation, metabolism and host immunity. This molecular crosstalk takes place not only in normal epithelial or tumor cells, but also in a plethora of immune cells from the adaptive and innate immune system in the tumor-stroma tissue microenvironment. Thus, the drugability of both the MAPK and the NHRSF pathways suggests potential for intervention therapies, especially for cancer immunotherapy. This review summarizes the existing literature covering the expression and function of NHRSF subclasses in human tumors, both solid and leukemias, and their effects in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).
三种主要的丝裂原活化蛋白激酶（MAPK）途径，ERK1/2、p38 和 JNK/SAPK，是核“激素”受体超家族（NHRSF）的上游调节剂，以乳腺癌中的雌激素受体为例。这些配体激活的转录因子发挥非基因组和基因组功能，它们通过磷酸化被翻译后修饰，或者直接与 MAPK 途径的成分相互作用，这些事件控制它们对参与细胞分化、增殖、代谢和宿主免疫的靶基因的转录活性。这种分子串扰不仅发生在正常的上皮或肿瘤细胞中，也发生在肿瘤基质组织微环境中的适应性和固有免疫系统的大量免疫细胞中。因此，MAPK 和 NHRSF 途径的药物可及性表明存在干预治疗的潜力，特别是用于癌症免疫治疗。这篇综述总结了现有的文献，涵盖了 NHRSF 亚类在人类肿瘤（实体瘤和白血病）中的表达和功能，以及它们与当前临床上批准的针对免疫检查点分子（如 PD1）的治疗药物联合使用的效果。
