Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma

Abstract

c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.

Keywords: Epstein–Barr virus; c-Jun N-terminal kinase; cancer cell survival; nasopharyngeal carcinoma; p38 mitogen-activated protein kinase.

Figure 1

JNK, p38 MAPK, and ERK pathways in MAPK signaling. Upon external stimulation, receptor tyrosine kinases (RTKs) activate the three-tiered kinase module comprising MAPKK,. MAPKK, and MAPK through sequential protein phosphorylation. The activated MAPKs translocate to the nucleus and trigger cellular responses.

Figure 2

The upstream activators and downstream targets of the JNK pathway. Several types of stimuli, such as inflammatory cytokines, tumor necrosis factor alpha (TNF-α), and growth factors, can induce activation of members of the MAPKKK family. Other factors such as oxidative stress and UV irradiation can also lead to MAPKKK activation. The scaffold protein JNK-interacting protein-1 (J1P) binds the MAPKKK and MAPKK family members with JNKs and facilitates the JNK activation. The activated JNKs may dissociate from this complex and induce mitochondria-dependent apoptosis through B cell lymphoma (BCL-2) and BCL-2 associated x-protein (BAX). On the other hand, activated JNKs may also promote transcription of genes involved in cell proliferation, differentiation, growth, and apoptosis via phosphorylation of the downstream targets.

Figure 3

p38 MAPKs pathway and its upstream and downstream activation. The four p38 MAPK family members (p38α, p38β, p38γ, and p38δ) are activated by external stress, inflammatory cytokines, or UV radiation, which is similar to the JNK pathway. Once activated, this pathway initiates production of the pro-apoptotic transcription factors for inflammation, differentiation, proliferation, apoptosis, senescence, and RNA splicing.