PMID:31489901

Citation	Albi, E, Cataldi, S, Ceccarini, MR, Conte, C, Ferri, I, Fettucciari, K, Patria, FF, Beccari, T and Codini, M (2019) Gentamicin Targets Acid Sphingomyelinase in Cancer: The Case of the Human Gastric Cancer NCI-N87 Cells. Int J Mol Sci 20
Abstract	Emerging literature implicates acid sphingomyelinase in tumor sensitivity/resistance to anticancer treatments. Gentamicin is a drug commonly used as an antimicrobial but its serendipity effects have been shown. Even though many evidences on the role of gentamicin in cancer have been reported, its mechanism of action is poorly understood. Here, we explored acid sphingomyelinase as a possible new target of gentamicin in cancer. Since gastric cancer is one of the most common cancers and represents the second cause of death in the world, we performed the study in NCI-N87 gastric cancer cell line. The effect of the drug resulted in the inhibition of cell proliferation, including a reduction of cell number and viability, in the decrease of MIB-1 proliferative index as well as in the upregulation of cyclin-dependent kinase inhibitor 1A and 1B ( and ), and growth arrest and DNA-damage 45A () genes. The cytotoxicity was apoptotic as shown by FACS analysis. Additionally, gentamicin reduced HER2 protein, indicating a minor tumor aggressiveness. To further define the involvement of sphingomyelin metabolism in the response to the drug, gene and protein expression of acid and neutral sphingomeylinase was analyzed in comparison with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and vitamin D receptor (VDR), molecules involved in cancer. Gentamicin induced a downregulation of , , and neutral sphingomyelinase and a strong upregulation of acid sphingomyelinase. Of note, we identified the same upregulation of acid sphingomyelinase upon gentamicin treatment in other cancer cells and not in normal cells. These findings provide new insights into acid sphingomyelinase as therapeutic target, reinforcing studies on the potential role of gentamicin in anticancer therapy.
Links	PubMed Online version:10.3390/ijms20184375
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:Q6I9V6		GO:0097472: cyclin-dependent protein kinase activity	ECO:0000180: clinical study evidence		F		Figure 1. Effects of increasing doses of gentamicin on NCI-N87 cells. (a) The cells were counted 24 and 72 h after treatment with increasing concentrations of the drug (0.25–2.0 mM) (lines referred to the ordinate on the right). Cell death was evaluated by trypan blue staining (histograms referred to the ordinate on the left). Ctr, untreated sample. (b) Cell viability was assessed by MTT method and expressed as a percentage relative to that of the control cells set at 100%. (c) FACS analysis. (d) CDKN1A, CDKN1B gene expression, data are referred to the gentamicin (GM)-untreated sample (control) set at 1.	complete

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