The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer
Laura García-Hernández1, María Belén García-Ortega2,3,4,5, Gloria Ruiz-Alcalá2,3,4,5
1Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.
Abstract:
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.
Insights
Mitogen-activated protein kinase (MAPK) pathways, particularly p38 kinases, are crucial in cancer signaling and therapy response. Understanding their complex roles and regulation offers potential for developing targeted cancer treatments.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Signal Transduction
Background:
- Mitogen-activated protein kinase (MAPK) pathways regulate cellular responses to external signals.
- p38 kinases, a key MAPK group, are implicated in various diseases, including cancer, often exhibiting dual roles.
- Dysregulation of MAPK signaling is a hallmark of cancer, affecting disease progression and treatment outcomes.
Purpose of the Study:
- To review the mechanisms of action and regulation of MAPK pathways, focusing on p38 kinases in cancer.
- To analyze the role of different p38 isoforms as potential biomarkers and therapeutic targets.
- To summarize current preclinical and clinical trials involving p38-targeted drugs for precision cancer medicine.
Main Methods:
- Literature review of MAPK signaling in cancer.
- Analysis of p38 kinase regulation, including microRNA involvement.
- Examination of p38 isoform expression and function across different tissues.
- Compilation of data from preclinical and clinical studies on p38 inhibitors.
Main Results:
- MAPK pathways, especially p38, are central to cancer cell signaling with complex, context-dependent functions.
- Extensive cellular regulation of p38 kinases, involving post-translational modifications and microRNAs, influences their activity.
- Specific p38 isoforms show differential expression and potential as biomarkers and therapeutic targets in various cancers.
- Ongoing clinical trials show promise for p38-targeted therapies in precision oncology.
Conclusions:
- p38 kinases represent a significant area for cancer research due to their multifaceted roles.
- Targeting p38 pathways holds potential for novel cancer therapies and personalized treatment strategies.
- Further investigation into MAPK regulation and isoform-specific functions is essential for advancing cancer treatment.
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