c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade

Abstract

Disseminated cancer cells rely on intricate interactions among diverse cell types in the tumor-associated stroma, vasculature, and immune system for survival and growth. Ubiquitous expression of c-Jun N-terminal kinase (jnk) genes in various cell types permits their control of metastasis. In early stages of metastasis, JNKs affect tumor-associated inflammation and angiogenesis as well as tumor cell migration and intravasation. Within the tumor stroma, JNKs are essential for the release of growth factors that promote epithelial-to-mesenchymal transition (EMT) in tumor cells. JNK3, the least ubiquitous isoform, facilitates angiogenesis by increasing endothelial cell migration. Importantly, JNK expression in tumor cells integrates stromal signals to promote tumor cell invasion. However, JNK isoforms differentially regulate migration toward the endothelial barrier. Once tumor cells enter the bloodstream, JNKs increase circulating tumor cell (CTC) survival and homing to tissues. By promoting fibrosis, JNKs improve CTC attachment to the endothelium. Once anchored, JNKs stimulate EMT to facilitate tumor cell extravasation and enhance the secretion of endothelial barrier disrupters. Tumor cells attract barrier-disrupting macrophages by JNK-dependent transcription of macrophage chemoattractant molecules. In the secondary tissue, JNKs are instrumental in the premetastatic niche and stimulate tumor cell proliferation. JNK expression in cancer cells stimulates tissue-remodeling macrophages to improve tumor colonization. However, in T-cells, JNKs alter cytokine production that increases tumor surveillance and inhibits the recruitment of tissue-remodeling macrophages. Therapeutically targeting JNKs for metastatic disease is attractive considering their promotion of metastasis; however, specific JNK tools are needed to determine their definitive actions within the context of the entire metastatic cascade.

DNA polymerase iota (Pol ι) promotes invasion and metastasis of esophageal squamous cell carcinoma

“…MMPs are a family of structurally related zinc-and calcium-dependent endopeptidases that enhance the progression of the epithelial-to-mesenchymal transition (EMT) [30, 31] via degrading various components of extracellular matrix (ECM) and promoting detachment of epithelial cells from the surrounding tissue [32]. MMP-2 and MMP-9 participate in proteolysis of major components of the basement membrane and are associated with tumor invasion and lymph node metastasis [33, 34].…”

“…Furthermore, when the JNK inhibitor was applied to the ESCC cells overexpressing Pol ι, the Pol ι-induced aggressive phenotype of enhanced cell motility and invasion was reversed. JNKs were initially identified as stress activated protein kinases (SPAK) and are highly activated by cellular stresses, such as DNA damage [35]. Interestingly, transforming growth factor (TGF) β-activated kinase 1 (TAK1) is activated by the DNA damage response, which in turn, phosphorylates and activates JNK [35, 36].…”

“…JNKs were initially identified as stress activated protein kinases (SPAK) and are highly activated by cellular stresses, such as DNA damage [35]. Interestingly, transforming growth factor (TGF) β-activated kinase 1 (TAK1) is activated by the DNA damage response, which in turn, phosphorylates and activates JNK [35, 36]. It remains unclear whether overexpression of Pol ι induces the DNA damage response, subsequently leading to the activation of TAK1-JNK signal pathway.…”

Curcumin Suppresses MAPK Pathways to Reverse Tobacco Smoke-induced Gastric Epithelial-Mesenchymal Transition in Mice

“…It has been established that MAPK pathways play central roles in tumorigenic process by promoting the development and progression of cancer. Evidences show that ERK1/2, JNK, p38, and ERK5 promote EMT (Antoon et al, ; Ebelt et al, ; Epstein Shochet et al, ; Knauf et al, ; Milone et al, ; Niu et al, ; Okada et al, ; Ramsay et al, ; Rhyu et al, ). In the present study, we revealed that TS‐induced gastric EMT was associated with upregulation of ERK1/2, p38, JNK, and ERK5 activation in vivo .…”

“…Numerous evidences have revealed that MAPKs promote EMT in various epithelial cells such as intestinal epithelial cells, hepatocellular carcinoma cells, and prostate cancer cells (Mulholland et al, ; Nagai et al, ; Uttamsingh et al, ). It has been showed that ERK1/2 (Knauf et al, ; Okada et al, ; Rhyu et al, ), p38 (Milone et al, ; Niu et al, ), and JNK pathways (Ebelt et al, ; Epstein Shochet et al, ) are critical in EMT regulation. ERK5 is the lesser studied MAPK pathway.…”