PUBLICATION
The dialkyl resorcinol stemphol disrupts calcium homeostasis to trigger programmed immunogenic necrosis in cancer
- Authors
- Ji, S., Lee, J.Y., Schrör, J., Mazumder, A., Jang, D.M., Chateauvieux, S., Schnekenburger, M., Hong, C.R., Christov, C., Kang, H.J., Lee, Y., Han, B.W., Kim, K.W., Shin, H.Y., Dicato, M., Cerella, C., König, G.M., Orlikova, B., Diederich, M.
- ID
- ZDB-PUB-171219-2
- Date
- 2017
- Source
- Cancer letters 416: 109-123 (Journal)
- Registered Authors
- Keywords
- Calcium, Cancer, Caspase-independent apoptosis, Leukemia, Programmed necrosis
- MeSH Terms
-
- A549 Cells
- Animals
- Apoptosis/drug effects*
- Calcium/metabolism*
- Cell Line, Tumor
- Cell Survival/drug effects
- Homeostasis/drug effects*
- Humans
- Jurkat Cells
- MCF-7 Cells
- Molecular Structure
- Necrosis
- Neoplasms/drug therapy*
- Neoplasms/metabolism
- Neoplasms/pathology
- Resorcinols/chemistry
- Resorcinols/pharmacology*
- THP-1 Cells
- U937 Cells
- Xenograft Model Antitumor Assays/methods
- Zebrafish
- PubMed
- 29246646 Full text @ Cancer Lett.
Citation
Ji, S., Lee, J.Y., Schrör, J., Mazumder, A., Jang, D.M., Chateauvieux, S., Schnekenburger, M., Hong, C.R., Christov, C., Kang, H.J., Lee, Y., Han, B.W., Kim, K.W., Shin, H.Y., Dicato, M., Cerella, C., König, G.M., Orlikova, B., Diederich, M. (2017) The dialkyl resorcinol stemphol disrupts calcium homeostasis to trigger programmed immunogenic necrosis in cancer. Cancer letters. 416:109-123.
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 Ca2+-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca2+ levels and computational docking confirmed binding of STP 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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping