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2-Hydroxy-oleic acid does not activate sphingomyelin synthase activity

Bin Lou1, Qi Liu2, Jiahui Hou2

  • 1From the School of Pharmacy, Fudan University, Shanghai 201203, China,.

The Journal of Biological Chemistry
|October 12, 2018
PubMed

Insights

2-Hydroxy-oleic acid (2OHOA) does not activate SMS enzymes as previously thought. Its anticancer effects may stem from reducing phosphatidylcholine levels, impacting cell membranes.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Pharmacology

Background:

  • 2-Hydroxy-oleic acid (2OHOA) is recognized for its anticancer properties, inducing apoptosis and cell cycle arrest.
  • Prior research suggested its mechanism involved sphingomyelin synthase (SMS) activation in cancer cells.

Purpose of the Study:

  • To investigate the proposed role of SMS activation in 2OHOA's anticancer effects.
  • To examine the impact of 2OHOA on sphingomyelin and phosphatidylcholine metabolism in cancer cells and in vivo.

Main Methods:

  • Treatment of A549 and U118 cancer cells with 2OHOA.
  • Measurement of SMS activity, sphingomyelin, and phosphatidylcholine levels.
  • Inhibition assays with recombinant SMS1 (rSMS1) and SMS2 (rSMS2).
  • In vivo studies involving oral administration of 2OHOA to C57BL/6J mice, assessing SMS activity, sphingomyelin, and lysophosphatidylcholine acyltransferase (LPCAT) activity.

Main Results:

  • 2OHOA did not activate SMS or increase sphingomyelin in treated cells or mouse tissues.
  • A significant reduction in phosphatidylcholine was observed in cancer cells treated with 2OHOA.
  • 2OHOA demonstrated dose-dependent inhibition of rSMS1 and rSMS2.
  • In vivo, 2OHOA did not affect liver/intestinal SMS activity or plasma sphingomyelin but inhibited LPCAT activity.

Conclusions:

  • 2OHOA is not an SMS activator; its anticancer effects are likely linked to phosphatidylcholine metabolism disruption.
  • The reduction in phosphatidylcholine may alter cell membrane properties, contributing to observed anticancer activity.
  • This finding reframes the understanding of 2OHOA's mechanism of action in cancer therapy.
Keywords:
2-hydroxy-oleic acid (2OHOA)anti-cancer drugcancerlipidlipid metabolismlysophosphatidylcholine acyltransferase (LPCAT)phosphatidylcholinephospholipidsphingolipidsphingomyelinsphingomyelin synthase (SMS)

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