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

Cancer Biology & Therapy
Xingfeng BaoKenichi Nomoto

Abstract

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-Golgi-network 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 PTEN-deficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward n...Continue Reading

References

Aug 1, 1996·Chemistry & Biology·D T HungS L Schreiber
Dec 30, 1998·Journal of Natural Products·J A BeutlerM R Boyd
Nov 24, 1999·The Journal of Biological Chemistry·S IsotaniK Yonezawa
Aug 3, 2004·Nature Reviews. Cancer·Besim Ogretmen, Yusuf A Hannun
Mar 23, 2005·Current Opinion in Cell Biology·Daniela HoellerIvan Dikic
Apr 2, 2005·Nature Reviews. Cancer·Ralf Küppers
Sep 9, 2006·Cell·Kazuaki Ohtsubo, Jamey D Marth
Mar 1, 2007·Journal of Natural Products·Brent J YoderDavid G I Kingston
May 24, 2008·Science·Yasemin SancakDavid M Sabatini
Dec 2, 2008·Nature Reviews. Drug Discovery·Inki KimJohn C Reed
Jun 26, 2009·Nature·Kenneth L ScottLynda Chin
Jul 7, 2009·Annual Review of Cell and Developmental Biology·Sumana Raychaudhuri, William A Prinz
Jul 10, 2009·Proceedings of the National Academy of Sciences of the United States of America·Xingfeng BaoMinoru Fukuda
Dec 23, 2009·The Journal of Cell Biology·Christopher S WoodChristopher G Burd
Aug 12, 2010·PLoS Genetics·Hiroyuki KobunaHiroyuki Arai
Aug 21, 2010·Bioorganic & Medicinal Chemistry·Joseph J TopczewskiDavid F Wiemer
Sep 8, 2010·Methods in Enzymology·David F SmithRichard D Cummings
Dec 22, 2010·Proceedings of the National Academy of Sciences of the United States of America·Bernhard KlooDaniel Krappmann
Jan 12, 2011·The Journal of Cell Biology·Ximing DuHongyuan Yang
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Jun 3, 2011·Lipids·Sarah A HolsteinRaymond J Hohl
Jul 19, 2011·Trends in Cell Biology·Felipe H Santiago-Tirado, Anthony Bretscher
Aug 9, 2011·Nature Chemical Biology·Anthony W G BurgettMatthew D Shair
Nov 17, 2011·Seminars in Cell & Developmental Biology·Pauline GonnordChristophe Lamaze
Dec 14, 2012·Nature Reviews. Cancer·Samy A F Morad, Myles C Cabot
May 4, 2013·Current Opinion in Cell Biology·Suzanne R Pfeffer
Jul 11, 2013·Proceedings of the National Academy of Sciences of the United States of America·Matthias PfeiferGeorg Lenz
Sep 6, 2013·The Journal of Organic Chemistry·John G Kodet, David F Wiemer

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Citations

Jun 6, 2015·Cancer Biology & Therapy·Ryan M SheehyRaymond J Hohl
Sep 30, 2017·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Jeff W StevensJosé A Morcuende
Jan 1, 2017·Journal of Cancer Prevention & Current Research·Karen L ChenZeynep Madak-Erdogan
Feb 23, 2020·The Journal of Biological Chemistry·Tiphaine PéresseBruno Mesmin
Sep 24, 2016·Clinical Science·Ugo Soffientini, Annette Graham
Oct 20, 2018·Lipids·Emily J KoubekRaymond J Hohl
Aug 3, 2019·European Journal of Medicinal Chemistry·Lucia BiasuttoMario Zoratti
Jan 29, 2021·The Journal of Biological Chemistry·Tiphaine PéresseBruno Mesmin
Jan 13, 2021·Journal of Natural Products·David G I Kingston
Jul 27, 2021·Frontiers in Genetics·Haiwei ZuoYong Xin
Oct 4, 2017·Journal of Natural Products·Tiphaine PéresseFanny Roussi
Oct 30, 2021·The Journal of Organic Chemistry·Chloe M SchroederDavid F Wiemer

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Methods Mentioned

BETA
glycosylation
fluorescence microscopy
flow cytometry
immunoprecipitation
ELISA
fluorescence imaging
surface plasmon resonance

Software Mentioned

R
In Cell Analyzer
BIACore
Corel PaintShop
FluorView

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