The p38 Pathway: From Biology to Cancer Therapy

Abstract

The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored.

Keywords: SAPK; cancer treatment; oncogenicity; p38 MAPK; phosphorylation; tumor suppressor.

Figure 1

p38 MAPK activation. (A) Canonical pathway: Several environmental stimuli activate p38 by phosphorylation of Thr180 and Tyr182 through MAP3Ks and MAP2Ks MKK3/6. Phosphatases PP2A/C, Wip1 and MKP/DUSP inhibit p38 activation. (B) Alternative pathways: Noncanonical p38 activation occurs in T-lymphocytes upon antigen presentation (TCR: antigen T cell receptor) and involves phosphorylation of Tyr323, which promotes an auto-phosphorylation loop. In addition, p38 can be activated by the presence of other stimuli such as intracellular infection, myocardial ischemia or dendritic cells (DCs) maturation signals. In these cases, TAB1 associates with p38, promoting its auto-phosphorylation. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 2

The dual role of p38 MAPK in tumorigenesis. (A) p38-dependent cellular. processes can be classified on the basis of the role they play during tumorigenesis. (B) p38 inhibits oncogenic transformation and promotes the progression of tumors in late stages of the disease. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.