Marizomib Promotes Senescence or Long-Term Apoptosis in Melanoma Cancer Cells

Abstract

Cellular senescence is cell cycle arrest and the inhibition of cell proliferation. New anticancer approaches include the elimination of cancer cells through the induction of senescence followed by senolysis. New prosenescence compounds are still being searched for. Little is known about the ability of proteasome inhibitors to induce senescence in tumor cells, especially in malignant melanoma. The aim of our study was to verify the activity of a natural proteasome inhibitor—marizomib (MZB)—directly after incubation and after its removal to assess its potential to induce senescence or long-term apoptosis in malignant melanoma cell lines (A375 and G361). After 48 h of incubation with MZB, we observed an increased number of SA-β-galactosidase-positive cells, upregulated expression of P21 and P-P53 proteins and an increased number of cells at the subG1 phase (line G361) or at both the subG1 and G2/M phases (line A375). After 96 h from inhibitor removal, the G361 line presented signs of senescence (increased level of SA-β-galactosidase, IL-8, P-P53, G2/M and S phases of cell cycle, decreased lamin B1 and cleaved lamin B1), while the A375 line demonstrated more signs of apoptosis (increased subG1 phase, P-P53, cleaved lamin B1). The gathered findings suggest that MZB resulted in the induction of cellular senescence (line G361) or enhanced apoptosis (line A375) in the melanoma cell lines tested here and could be a promising therapeutic factor in malignant melanoma treatment.

Keywords

• proteasome inhibition
• senescence
• apoptosis
• cancer treatment
• salinosporamide A
• NPI-0052