Inhibition of p38/MK2 Signaling Prevents Vascular Invasion of Melanoma

Abstract

Melanoma cells can switch between distinct gene expression profiles, resulting in proliferative or invasive phenotypes. Signaling pathways involved in this switch were analyzed by gene expression profiling of a cohort of 22 patient-derived melanoma cell lines. CDH1 negativity was identified as a surrogate marker for the invasive phenotype. CDH1 expression could be turned on and off by modulating activity of p38 or its downstream target MK2, suggesting that this pathway controls melanoma progression. Mechanistically, MK2 inhibition prevented melanoma-induced vascular barrier disruption, reduced the expression of PODXL and DEL-1, and prevented vascular dissemination in vivo. PODXL and DEL-1 expression in patients with melanoma were associated with poor survival and thus can be used as prognostic markers. Downstream targets of MK2 may thus serve as candidate therapeutics.

NRASQ61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells

“…Surprisingly, the positive correlation between high phospho‐p38α and high phospho‐JNK contrasts with a previously published study focused on BRAF mutant melanoma (Wenzina et al., 2020). Although our findings suggest a tumor suppressive role of p38α in NRAS‐mutated melanoma, it might have a different role in a BRAF mutant background.…”

“…The p38 pathway has been most frequently associated with a tumor suppressor function by negatively regulating cell survival and proliferation (Han & Sun, 2007). Although it has been suggested that modulating p38 or its downstream targets, PODXL, and DEL‐1 can serve as candidate therapeutics in melanoma (J. Wenzina et al., 2020), the role of p38α in melanoma is unclear and needs further investigation. We therefore hypothesized that p38α was a tumor suppressor in NRAS‐mutant melanoma.…”

Melanoma cells release DEL-1 via small extracellular vesicles

“…To analyze if DEL-1 is released via an endosomal pathway, we assessed its subcellular distribution prior to its release into the extracellular space. VM14 melanoma cells (8), which do not release DEL-1-positive sEV (Supp. Fig.…”

“…DEL-1 detected in small extracellular vesicles (sEV) isolated from plasma has been identified as a biomarker for early breast cancer detection (7). In melanoma cells DEL-1 is a marker for invasive behavior and high mRNA expression in melanoma samples is associated with poor patient survival (8). However, the anti-inflammatory function of DEL-1 complicates the interpretation of effects of DEL-1 in cancer as shown in a mouse model.…”

Juniperus indica Bertol. extract synergized with cisplatin against melanoma cells via the suppression of AKT/mTOR and MAPK signaling and induction of cell apoptosis

“…Previous results showed that the MAPK pathway in melanoma cells is highly activated and ERK, p38, and JNK proteins are overexpressed in the tumor mass of patients that are correlated with drug resistance and reduce the survival benefits of patients [40]. For instance, BRAF inhibition results in a rapid recovery of phospho-ERK (pERK) signaling result in drug resistance [41]; activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas [42,43]; p38 activity contribute to metastasis result in poor prognosis [44]. Numerous observations indicate a growth-promoting role of JNK in various cell types such as hepatocarcinoma cells, fibroblasts, immortalized neural stem cells and melanoma cells and have reported that active ERK indirectly facilitates the JNK activity and enforces JNK-Jun signaling to elevate cyclin D1 expression result in cell cycle progression [45].…”