Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking.
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 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.
a Eisai Inc. ; Andover , MA , USA.
Xingfeng
X
Bao
Wanjun
W
Zheng
Naoko
N
Hata Sugi
Kishan L
KL
Agarwala
Qunli
Q
Xu
Zichun
Z
Wang
Karen
K
Tendyke
Winnie
W
Lee
Lana
L
Parent
Wei
W
Li
Hongsheng
H
Cheng
Yongchun
Y
Shen
Noel
N
Taylor
Zoltan
Z
Dezso
Hong
H
Du
Yoshihiko
Y
Kotake
Nanding
N
Zhao
John
J
Wang
Maarten
M
Postema
Mary
M
Woodall-Jappe
Yasutaka
Y
Takase
Toshimitsu
T
Uenaka
David G I
DG
Kingston
Kenichi
K
Nomoto
D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D021601:trans-Golgi Network / Q000187:drug effects*
D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054852:Small Molecule Libraries; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human
ConA concanavalin; DLBCL diffuse large B cell lymphoma; MAA Maackia amurensis agglutinin; ORPs oxysterol-binding protein related family proteins; PDK1 phosphoinositide-dependent kinase 1; PIP3 phosphatidylinositol (3,4,5)-triphosphate; PNA peanut agglutinin; PTEN phosphatase and tensin homolog; SA-J schweinfurthin A-J; TGN trans-Golgi-network; WGA wheat germ agglutinin; diffuse large B cell lymphoma; mTOR mammalian target of rapamycin; mTOR-AKT signaling; natural compounds; schweinfurthins; trans-Golgi-network