Abstract
Simple SummaryStress-activated c-Jun N-terminal kinases (JNKs) are members of mitogen-activated protein kinases (MAPKs). Apart from having both tumor promoting and tumor suppressing roles in cancers due to its impact on apoptosis and autophagy pathways, JNK also plays complex roles in the heterogeneous tumor microenvironment (TME) and is involved in different tumorigenesis pathways. The JNK pathway influences various stressful and chronic inflammatory conditions along with different cell populations in TME. In this review, we aim to present the current knowledge of JNK-mediated processes in TME and the challenges in clinical translation.The c-Jun N-terminal kinases (JNKs) are a group of mitogen-activated protein kinases (MAPKs). JNK is mainly activated under stressful conditions or by inflammatory cytokines and has multiple downstream targets for mediating cell proliferation, differentiation, survival, apoptosis, and immune responses. JNK has been demonstrated to have both tumor promoting and tumor suppressing roles in different cancers depending on the focused pathway in each study. JNK also plays complex roles in the heterogeneous tumor microenvironment (TME). JNK is involved in different tumorigenesis pathways. TME closely relates with tumor development and consists of various stressful and chronic inflammatory conditions along with different cell populations, in which the JNK pathway may have various mediating roles. In this review, we aim to summarize the present knowledge of JNK-mediated processes in TME, including hypoxia, reactive oxygen species, inflammation, immune responses, angiogenesis, as well as the regulation of various cell populations within TME. This review also suggests future research directions for translating JNK modulation in pre-clinical findings to clinical benefits.
Highlights
We subsequently discovered that the Jun N-terminal kinases (JNKs) pathway mediates low oxygen level induced epithelial–mesenchymal transition (EMT) and stemness maintenance in colorectal cancer (CRC) cell lines HT-29, DLD-1, and SW-480 [26]
Studied the role of the JNK pathway in reactive oxygen species (ROS)-induced cell death among CRC, hepatocellular carcinoma (HCC), and cervical cancer cells. They concluded that JNK-associated leucine zipper protein (JLP)-JNK pathway was activated by hydrogen peroxide
The group further concluded that p38 mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and phosphoinositide 3-kinase (PI3K) did not participate in the process
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. MKK4 and MKK7 can be activated by a number of MKK kinases (MAP3Ks), Cancers 2021, 13, 2196. MKK4 and MKK7 can be activated by a number of MKK kinases (MAP3Ks), including transforming growth factor-β-activated kinase 1. (TAK1/MAP3K7) and apoptosis signal-regulating kinase 1 (ASK1/MAP3K5). TAK1 activates JNK via inflammatory cytokines (interleukin-1 (IL-1), lymphotoxin-b, transforming including transforming growth factor-β-activated kinase 1 (TAK1/MAP3K7) and apoptosis growth factor-β signal-regulating (TGF-β), tumorkinase necrosis factor-α (TNF-α)), and tollJNK receptors (TLR-3, 4cy (ASK1/MAP3K5). ASK1 responds to oxidative stress and TAK1 encould transduce signals from various receptor systems in both the innate and adaptive doplasmic reticulum stress [7]. MAP3Ks, including MAP3K1, MAP3K4, dual leucine zipper kinase (DLK), and induced by stresses such as ultraviolet irradiation, DNA damage, receptors, andsuch hor-as mixed-lineage kinase 3 (MLK3), can activate.
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