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Abstract
2-Hydroxy-oleic acid (2OHOA) is a potent anticancer drug that induces cancer cell cycle arrest and apoptosis. Previous studies have suggested that 2OHOA's anticancer effect is mediated by SMS activation in cancer cells, including A549 and U118 cells. To confirm this phenomenon, in this study, we treated both A549 and U118 cells with 2OHOA and measured SMS activity. To our surprise, we found neither 2OHOA-mediated SMS activation nor sphingomyelin accumulation in the cells. However, we noted that 2OHOA significantly reduces phosphatidylcholine in these cells. We also did not observe 2OHOA-mediated SMS activation in mouse tissue homogenates. Importantly, 2OHOA inhibited rather than activated recombinant SMS1 (rSMS1) and rSMS2 in a dose-dependent fashion. Intra-gastric treatment of C57BL/6J mice with 2OHOA for 10 days had no effects on liver and small intestine SMS activities and plasma sphingomyelin levels. The treatment inhibited lysophosphatidylcholine acyltransferase (LPCAT) activity, consistent with the aforementioned reduction in plasma phosphatidylcholine. Because total cellular phosphatidylcholine is used as a predictive biomarker for monitoring tumor responses, the previously reported 2OHOA-mediated cancer suppression could be related to this phosphatidylcholine reduction, which may influence cell membrane structure and properties. We conclude that 2OHOA is not a SMS activator and that its anticancer property may be related to an effect on phosphatidylcholine metabolism.
Highlights
2-Hydroxy-oleic acid (2OHOA) is a potent anticancer drug that induces cancer cell cycle arrest and apoptosis
These results indicate that 2OHOA cannot stimulate sphingomyelin synthase (SMS) activity in our tested cancer cells and macrophages
We have reported that inhibition of SMS activity can reduce atherogenic lipoprotein production and attenuate endotoxinmediated macrophage inflammation [12, 24, 25]
Summary
Previous studies have suggested that 2OHOA’s anticancer effect is mediated by SMS activation in cancer cells, including A549 and U118 cells. 3 The abbreviations used are: 2OHOA, 2-hydroxy-oleic acid; PC, phosphatidylcholine; SM, sphingomyelin; SMS, sphingomyelin synthase; rSMS1 and rSMS2, recombinant SMS1 and SMS2, respectively; LPCAT, lysophosphatidylcholine acyltransferase; NBD, 12-(N-methyl-N-(7-nitrobenz-2-oxa-1,3diazol-4-yl)); MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium. The underlying mechanisms leading to cancer cell death remain largely unknown, it has been reported that the effect was mediated by activation of sphingomyelin synthase (SMS) in cancer cells and accumulation of cell sphingomyelin levels [6].
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