Natural products reveal cancer cell dependence on oxysterol-binding proteins

Burgett, Anthony W. G.; Poulsen, Thomas B.; Wangkanont, Kittikhun; Anderson, D Ryan; Kikuchi, Chikako; Shimada, Kousei; Okubo, Shuichi; Fortner, Kevin C.; Mimaki, Yoshihiro; Kuroda, Minpei; Murphy, Jason; Schwalb, David J.; Petrella, Eugene C.; Cornella-Taracido, Ivan; Schirle, Markus; Tallarico, John A.; Shair, Matthew D.

doi:10.1038/nchembio.625

Cited by 230 publications

(282 citation statements)

References 47 publications

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“…ORP4 could have an essential sterol and/or PI-4P transfer or sensing activity that has been re-established in immortalized and transformed cells to provide a growth advantage. In this regard, a series of natural products, collectively termed ORPphilins and including the bis-steroidal cephalostatin, exert their antiproliferative effects by inhibiting OSBP or ORP4L expression and activity (21). The possibility that the antineoplastic activity of these compounds is mediated by inhibiting ORP4L is supported by our RNAi findings.…”

Section: Discussionsupporting

confidence: 68%

“…OSBP and ORP4 were recently implicated in the anticancer activity of a set of natural products (21). Cephalostatin, OSW-1, ritterazine B, and schweinfurthin A, collectively termed ORPphilins, competitively inhibited 25-hydroxycholesterol (25OH) binding to OSBP and ORP4L with affinities that correlated with their cytotoxic activity.…”

Section: Oxysterol-binding Protein (Osbp) and Osbp-related Proteins (mentioning

confidence: 99%

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Oxysterol-binding Protein (OSBP)-related Protein 4 (ORP4) Is Essential for Cell Proliferation and Survival

Charman¹,

Colbourne²,

Pietrangelo³

et al. 2014

Journal of Biological Chemistry

119

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Background:The function of oxysterol-binding protein-related protein (ORP4) is unknown. Results: Silencing ORP4L or all ORP4 isoforms triggers growth arrest and apoptosis, which is suppressed by H-Ras and involves the C-terminal lipid binding domain. Conclusion: ORP4 is a sterol and PI-4P-binding protein required for survival and proliferation of immortalized and transformed cells. Significance: This is the first study to identify a mammalian ORP with growth regulatory activity.

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Oxysterol-binding Protein (Osbp) and Osbp-related Proteins (mentioning

confidence: 99%

Oxysterol-binding Protein (OSBP)-related Protein 4 (ORP4) Is Essential for Cell Proliferation and Survival

Charman¹,

Colbourne²,

Pietrangelo³

et al. 2014

Journal of Biological Chemistry

119

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show abstract

“…Understanding the functional roles of ORPs has taken on a new imperative with the recent discovery that human ORPs are specific targets of ORPphilins, a diverse group of nanomolar inhibitors that prevent cancer cell growth (68). In some cases, these compounds vaguely resemble a sterol fused to a PIP, implying that they confer inhibition by simultaneously occupying both sterol-and PI4P-binding sites.…”

Section: Do Osh Proteins Provide a Valid Model For Orp Functions In Omentioning

confidence: 99%

A Detour for Yeast Oxysterol Binding Proteins

Beh

McMaster

Kozminski

et al. 2012

Journal of Biological Chemistry

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Oxysterol binding protein-related proteins, including the yeast proteins encoded by the OSH gene family (OSH1-OSH7), are implicated in the non-vesicular transfer of sterols between intracellular membranes and the plasma membrane. In light of recent studies, we revisited the proposal that Osh proteins are sterol transfer proteins and present new models consistent with known Osh protein functions. These models focus on the role of Osh proteins as sterol-dependent regulators of phosphoinositide and sphingolipid pathways. In contrast to their posited role as non-vesicular sterol transfer proteins, we propose that Osh proteins coordinate lipid signaling and membrane reorganization with the assembly of tethering complexes to promote molecular exchanges at membrane contact sites.

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“…Interestingly, OSBP and ORP4L, 2 members of the oxysterol-binding protein related family proteins (ORPs) were reported as potential targets for SA and for a few other natural compounds that showed a similar anti-proliferative pattern in the NCI-60 cancer cell panel. 8 ORP family proteins have over 15 members and are conserved from C. elegans to humans, but have poorly defined functions in cancer cell survival and growth. 9 These studies have provided valuable insights about mechanism of the compounds, but have not yet explained the selective anti-proliferative activity of schweinfurthins.…”

Section: Introductionmentioning

confidence: 99%

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Bao

Zheng

Sugi

et al. 2015

Cancer Biology & Therapy

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Abbreviations: SA-J schweinfurthin A-J; TGN trans-Golgi-network; PTEN phosphatase and tensin homolog; DLBCL diffuse large B cell lymphoma; mTOR mammalian target of rapamycin; PDK1 phosphoinositide-dependent kinase 1; PIP3 phosphatidylinositol (3,4,5)-triphosphate; WGA wheat germ agglutinin; ConA concanavalin; MAA Maackia amurensis agglutinin; PNA peanut agglutinin; ORPs oxysterol-binding protein related family proteins Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golginetwork trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTENdeficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/ AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.

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Natural products reveal cancer cell dependence on oxysterol-binding proteins

Cited by 230 publications

References 47 publications

Oxysterol-binding Protein (OSBP)-related Protein 4 (ORP4) Is Essential for Cell Proliferation and Survival

Oxysterol-binding Protein (OSBP)-related Protein 4 (ORP4) Is Essential for Cell Proliferation and Survival

A Detour for Yeast Oxysterol Binding Proteins

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

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