MEL-JUSO

Extracellular Acidosis Leads to Reduced Proliferation and G1/G0 Cell Cycle Arrest

Solid tumors such as malignant melanoma produce acidosis within their microenvironment because of metabolic alterations that occur in cancer cells. Research demonstrates that acidosis produces varied outcomes which include promoting tumor invasiveness and metastasis as well as triggering cell apoptosis and autophagy. Böhme et al. focused on the effects of prolonged extracellular acidosis on melanoma cells, hypothesizing they are constantly subjected to an acidic environment in vivo. Three melanoma cell lines (Mel Im, SKMel28, and Mel Juso) were treated with a MES-acidified RPMI medium at pH 6.7 for over two months. Notably, prolonged acidosis led to morphological changes, like enlarged cell bodies and branched extensions in these cells (Fig. 1a, arrows). All tested cell lines showed a marked decrease in proliferation, indicating a slow-cycling phenotype (Fig. 1b, LT pH 6.7). No apoptosis was induced during this period. The use of flow cytometry combined with propidium iodide staining showed elevated numbers of cells in the G1/G0 phase with fewer S-phase cells which suggests that cells were arrested in the G1/G0 phase (Fig. 1c and d).

Fig. 1. Long-time acidosis mediates morphological alterations, reduction of proliferative activity, and G1/G0 cell cycle arrest (Böhme I and Bosserhoff A, 2019).

NO-SERM 4d Reduces Prometastatic Behavior of Melanoma Cells

The incidence of malignant melanoma is increasing, with survival rates declining significantly at advanced stages. Currently, available therapies often cause severe side effects and may lead to resistance. Estrogens potentially play roles in melanoma growth, influenced by ERα and ERβ pathways. Bechmann et al. used retrospective data analysis from TCGA to assess ER expressions in melanoma patients. It further evaluated the impact of ERβ-specific targeting through a nitric oxide-releasing selective ER modulator, NO-SERM 4d, on cellular behaviors linked to metastasis (Fig. 2a). Two melanoma cell lines, A2058 and MEL-JUSO, with similar ERα/ERβ levels but different receptor localizations, were used. A concentration of 10 μM NO-SERM 4d, known to not affect proliferation, was applied. Treatment significantly reduced motility, migration, and invasion in both cell lines (Fig. 2b–d). In A2058 cells, NO-SERM 4d significantly decreased adhesion to fibronectin, while MEL-JUSO showed a similar trend (Fig. 2e). These results suggest that inhibiting ERβ impacts various steps of the invasion–metastasis cascade in melanoma cells.

Fig. 2. Impact of NO-SERM 4d (10 μM) on prometastatic behavior of melanoma cell models (Bechmann N, Calsina B, et al., 2022).