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

Authors
  • Ji, Seungwon1
  • Lee, Jin-Young
  • Schrör, Jan
  • Mazumder, Aloran
  • Jang, Dong Man
  • Chateauvieux, Sébastien
  • Schnekenburger, Michael
  • Hong, Che Ry
  • Christov, Christo
  • Kang, Hyoung Jin
  • Lee, Youngjo
  • Han, Byung Woo
  • Kim, Kyu-Won
  • Shin, Hee-Young
  • Dicato, Mario
  • Cerella, Claudia
  • König, Gabriele M.
  • Orlikova, Barbora
  • Diederich, Marc1
Type
Published Article
Journal
Cancer Letters
Publisher
Elsevier
Publication Date
Mar 04, 2018
Volume
416
Pages
109–123
Identifiers
DOI: 10.1016/j.canlet.2017.12.011
Source
LBMCC
Keywords
License
White

Abstract

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 STP-induced non-canonical programmed cell death was Ca 2þ-dependent but independent of cas-pases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca 2þ levels and computational docking confirmed binding of STP within the thap-sigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca 2þ-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca 2þ accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron mi-croscopy. Confocal fluorescent microscopy allowed identifying mitochondrial Ca 2þ overload as initiator of STP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that STP-induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly , the translational immunogenic potential of STP was validated by HMGB1 release of STP-treated AML patient cells. STP reduced colony and in vivo tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish.

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