ferrostatin-1 and Melanoma

In this study, we evaluated the anti-tumor effects of dioscin, a steroidal saponin, on melanoma cells. Dioscin significantly inhibited cell viability and induced cell death of melanoma cells in a time- and dose- dependent manner. Furthermore, dioscin increased the concentration of intracellular ferrous irons, MDA and ROS. This effect could be inhibited by L-g-glutamyl-p-nitroanilide (GPNA), compound 968 and ferroptosis inhibitor ferrostatin-1 (Fer-1). Furthermore, dioscin induced ferroptosis by affecting the expression of transferrin and ferroportin which are regulators of intracellular levels of iron. Finally, dioscin in combination with various chemotherapeutic agents showed synergistic effects against melanoma cells. Our data suggested that dioscin exerted anti-tumor effects in melanoma cells by inducing ferroptosis. Dioscin alone or with other agents might be applied as a promising strategy to treat melanoma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzophenanthridines; Cation Transport Proteins; Cell Death; Cell Line, Tumor; Cell Survival; Cyclohexylamines; Diosgenin; Drug Synergism; Ferroptosis; Humans; Iron; Malondialdehyde; Melanoma; Phenylenediamines; Reactive Oxygen Species; RNA, Small Interfering; Transferrin

Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. This form of iron-dependent cell death is morphologically and genetically distinct from apoptosis, necroptosis, and autophagy. miRNAs are known to play crucial roles in diverse fundamental biological processes. However, to date no study has reported miRNA-mediated regulation of ferroptosis. Here we show that miR-137 negatively regulates ferroptosis by directly targeting glutamine transporter SLC1A5 in melanoma cells. Ectopic expression of miR-137 suppressed SLC1A5, resulting in decreased glutamine uptake and malondialdehyde (MDA) accumulation. Meanwhile, antagomir-mediated inactivation of endogenous miR-137 increased the sensitivity of melanoma cells to erastin- and RSL3-induced ferroptosis. Importantly, knockdown of miR-137 increased the antitumor activity of erastin by enhancing ferroptosis both in vitro and in vivo. Collectively, these data indicate that miR-137 plays a novel and indispensable role in ferroptosis by inhibiting glutaminolysis and suggest a potential therapeutic approach for melanoma.

Topics: 3' Untranslated Regions; Amino Acid Transport System ASC; Animals; Antagomirs; Apoptosis; Cell Line, Tumor; Cyclohexylamines; Ferrous Compounds; Glutamine; Humans; Lipid Peroxidation; Malondialdehyde; Melanoma; Mice; Mice, Nude; MicroRNAs; Minor Histocompatibility Antigens; Phenylenediamines; Piperazines; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering