Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.
Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain.
Int J Mol Sci. 2021 Dec 29;23(1):370. doi: 10.3390/ijms23010370.
The mitogen-activated protein kinase (MAPK) family is an important bridge in the transduction of extracellular and intracellular signals in different responses at the cellular level. Within this MAPK family, the p38 kinases can be found altered in various diseases, including cancer, where these kinases play a fundamental role, sometimes with antagonistic mechanisms of action, depending on several factors. In fact, this family has an immense number of functionalities, many of them yet to be discovered in terms of regulation and action in different types of cancer, being directly involved in the response to cancer therapies. To date, three main groups of MAPKs have been identified in mammals: the extracellular signal-regulated kinases (ERK), Jun N-terminal kinase (JNK), and the different isoforms of p38 (α, β, γ, δ). In this review, we highlight the mechanism of action of these kinases, taking into account their extensive regulation at the cellular level through various modifications and modulations, including a wide variety of microRNAs. We also analyze the importance of the different isoforms expressed in the different tissues and their possible role as biomarkers and molecular targets. In addition, we include the latest preclinical and clinical trials with different p38-related drugs that are ongoing with hopeful expectations in the present/future of developing precision medicine in cancer.
丝裂原活化蛋白激酶（MAPK）家族是细胞水平不同反应中外源和内源信号转导的重要桥梁。在这个 MAPK 家族中，p38 激酶在各种疾病中发生改变，包括癌症，这些激酶在癌症中起着重要作用，有时具有拮抗作用机制，这取决于多种因素。事实上，这个家族具有无数的功能，其中许多功能在不同类型的癌症中的调控和作用方面尚未被发现，它们直接参与癌症治疗的反应。迄今为止，哺乳动物中已经确定了三种主要的 MAPK 组：细胞外信号调节激酶（ERK）、Jun N-末端激酶（JNK）和不同的 p38 同工型（α、β、γ、δ）。在这篇综述中，我们强调了这些激酶的作用机制，考虑到它们在细胞水平上通过各种修饰和调节的广泛调控，包括各种各样的 microRNAs。我们还分析了在不同组织中表达的不同同工型的重要性及其作为生物标志物和分子靶标的可能作用。此外，我们还包括了目前正在进行的不同与 p38 相关的药物的最新临床前和临床试验，这些试验在癌症精准医学的现在/未来中有着充满希望的期望。
