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.

p38β and Cancer: The Beginning of the Road

“…Activation of MAP2Ks occurs by phosphorylation of two conserved S and T residues on their activation loop by a broad range of MAPK3s. The MAP3Ks of this pathway include ASK1 (apoptosis signal-regulating kinase 1), DLK1 (dual-leucine-zipper bearing kinase 1), TAK1 (transforming growth factor β-activated kinase 1), TAO (thousand and one amino acid) 1 and 2, TPL2 (tumor progression loci 2), MLK3 (mixed-lineage kinase 3), MEKK (3 and 4), and ZAK1 (leucine zipper and sterile-α motif kinase 1) [ 13 ]. However, it has also been reported activation/inactivation of this signaling pathway by non-canonical mechanisms as in the case of T-cell receptor [ 14 ] or GRK2 [ 15 ].…”

“…Since the mid-90s, when the p38MAPK signaling pathway was initially related to the cellular response to DNA damage agents including antitumor treatments [ 65 ], up to recent evidence indicating its use as a potential therapeutic target [ 13 ], the role of the p38MAPK signaling pathway in cancer has been deeply studied. However, most of the work has been focused on p38α, which has been repeatedly shown to play an important role in cancer biology.…”

A Middle-Out Modeling Strategy to Extend a Colon Cancer Logical Model Improves Drug Synergy Predictions in Epithelial-Derived Cancer Cell Lines

“…Specifically, four, three and two different drugs were targeting the PI3K/AKT, JNK/p38, and JAK/STAT modules, respectively. As many times cancer therapies take advantage of the dependency of cancer cells on an oncogene and/or loss of a tumor suppressor, and with the aforementioned pathways being among the most frequently altered pathways in several types of cancer, it is expected that multiple drugs have been designed to target these specific pathways (Thomas et al, 2015;Mayer and Arteaga, 2016;Martínez-Limón et al, 2020). The remaining seven modules included only one drug target each.…”

The regulation of Net1/Cdc14 by the Hog1 MAPK upon osmostress unravels a new mechanism regulating mitosis

“…However, it is activated and responds to other stimuli such as cytokines, DNA damage, oxidative and heat stress [15,16]. The core structure of the p38 pathway is similar to that of HOG in yeast [17], although the activation mechanism is not totally understood. In vivo replacement of components of the HOG pathway in S. cerevisiae by their mammalian counterparts demonstrated that there is a strong functional preservation of these MAPK pathways from yeast to mammals [14,18].…”