Natural products reveal cancer cell dependence on oxysterol-binding proteins.

Abstract

Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.

• Authors: Anthony W G Burgett, Thomas B Poulsen, Kittikhun Wangkanont, D Ryan Anderson, Chikako Kikuchi, Kousei Shimada, Shuichi Okubo, Kevin C Fortner, Yoshihiro Mimaki, Minpei Kuroda, Jason P Murphy, David J Schwalb, Eugene C Petrella, Ivan Cornella-Taracido, Markus Schirle, John A Tallarico, Matthew D Shair
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 7 Issue 9 Pg. 639-47 (Aug 07 2011) ISSN: 1552-4469 [Electronic] United States
• PMID: 21822274 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biological Products
• Carrier Proteins
• Cholestenones
• Hydroxycholesterols
• Phenazines
• Receptors, Steroid
• Saponins
• Sphingomyelins
• Spiro Compounds
• Steroids
• Stilbenes
• oxysterol binding protein
• ritterazine B
• schweinfurthin A
• cephalostatin I
• OSW 1
• 25-hydroxycholesterol

Topics

• Biological Products (antagonists & inhibitors, pharmacology)
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cholestenones (antagonists & inhibitors, pharmacology)
• Humans
• Hydroxycholesterols (pharmacology)
• Lipid Metabolism (drug effects)
• Neoplasms (metabolism)
• Phenazines (antagonists & inhibitors, pharmacology)
• Receptors, Steroid (genetics, metabolism)
• Saponins (antagonists & inhibitors, pharmacology)
• Signal Transduction (drug effects)
• Sphingomyelins (biosynthesis)
• Spiro Compounds (antagonists & inhibitors, pharmacology)
• Steroids (antagonists & inhibitors, pharmacology)
• Stilbenes (antagonists & inhibitors, pharmacology)