The dialkyl resorcinol stemphol disrupts calcium homeostasis to trigger programmed immunogenic necrosis in cancer

被引：20

作者：

Ji, Seungwon ^{[1
]}

Lee, Jin-Young ^{[1
]}

Schroer, Jan ^{[2
]}

Mazumder, Aloran ^{[1
]}

Jang, Dong Man ^{[1
]}

Chateauvieux, Sebastien ^{[1
,3
]}

Schnekenburger, Michael ^{[1
,3
]}

Hong, Che Ry ^{[4
]}

Christov, Christo ^{[5
]}

Kang, Hyoung Jin ^{[4
]}

Lee, Youngjo ^{[6
]}

Han, Byung Woo ^{[1
]}

Kim, Kyu-Won ^{[7
,8
]}

Shin, Hee-Young ^{[4
]}

Dicato, Mario ^{[3
]}

Cerella, Claudia ^{[1
,3
]}

Koenig, Gabriele M. ^{[2
]}

Orlikova, Barbora ^{[1
]}

Diederich, Marc ^{[1
,3
]}

机构：

[1] Seoul Natl Univ, Coll Pharm, Dept Pharm, Bldg 29,Room 223,1 Gwanak Ro, Seoul 08626, South Korea

[2] Univ Bonn, Inst Pharmaceut Biol, Nussallee 6, D-53115 Bonn, Germany

[3] Hop Kirchberg, Lab Biol Mol Canc, 9 Rue Edward Steichen, L-2540 Luxembourg, Luxembourg

[4] Seoul Natl Univ, Childrens Hosp, Coll Med, Dept Pediat,Canc Res Inst, Seoul, South Korea

[5] Univ Lorraine, Fac Med, Nancy, France

[6] Seoul Natl Univ, Dept Stat, 1 Gwanak Ro, Seoul 08626, South Korea

[7] Seoul Natl Univ, SNU Harvard Neurovasc Protect Ctr, Coll Pharm, Seoul, South Korea

[8] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul, South Korea

来源：

CANCER LETTERS | 2018年 / 416卷

基金：

新加坡国家研究基金会;

关键词：

Calcium; Caspase-independent apoptosis; Programmed necrosis; Leukemia; Cancer; CELL-DEATH; CALRETICULIN EXPOSURE; PERMEABILITY TRANSITION; CA2+ TRANSPORT; MITOCHONDRIA; MECHANISMS; APOPTOSIS; THAPSIGARGIN; INHIBITION; RESISTANCE;

D O I：

10.1016/j.canlet.2017.12.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Stemphol (STP) is a novel druggable phytotoxin triggering mixed apoptotic and non-apoptotic necrotic like cell death in human acute myeloid leukemia (AML). Use of several chemical inhibitors highlighted that SIP-induced non-canonical programmed cell death was Ca2+-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, SIP led to increased cytosolic Ca2+ levels and computational docking confirmed binding of SIP within the thapsigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca2+ accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron microscopy, Confocal fluorescent microscopy allowed identifying mitochondrial Ca2+ overload as initiator of SIP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that SIP induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly, the translational immunogenic potential of SIP was validated by HMGB1 release of STP-treated AML patient cells. SIP reduced colony and in vivo tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish. (C) 2017 Elsevier B.V. All rights reserved.

引用

页码：109 / 123

页数：15

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