PUBLICATION
Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer
- Authors
- Lee, J.Y., Talhi, O., Jang, D., Cerella, C., Gaigneaux, A., Kim, K.W., Lee, J.W., Dicato, M., Bachari, K., Han, B.W., Silva, A.M.S., Orlikova, B., Diederich, M.
- ID
- ZDB-PUB-171219-6
- Date
- 2017
- Source
- Cancer letters 416: 94-108 (Journal)
- Registered Authors
- Keywords
- BH3 mimetics, KRAS mutation, STAT3, coumarin, immunogenic cell death, non-small cell lung cancer
- MeSH Terms
-
- 4-Hydroxycoumarins/administration & dosage
- 4-Hydroxycoumarins/chemistry
- A549 Cells
- Animals
- Antineoplastic Combined Chemotherapy Protocols/pharmacology*
- Cell Death/drug effects
- Cell Line
- Cell Line, Tumor
- Cell Survival/drug effects
- Cytostatic Agents/administration & dosage
- Cytostatic Agents/chemistry
- Drug Synergism
- Endoplasmic Reticulum Stress/drug effects*
- Golgi Apparatus/metabolism
- Humans
- Lung Neoplasms/drug therapy*
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Molecular Structure
- Peptide Fragments/chemistry
- Peptidomimetics/administration & dosage
- Peptidomimetics/chemistry
- Proto-Oncogene Proteins/chemistry
- STAT3 Transcription Factor/antagonists & inhibitors*
- STAT3 Transcription Factor/metabolism
- Xenograft Model Antitumor Assays*
- Zebrafish
- PubMed
- 29247826 Full text @ Cancer Lett.
Citation
Lee, J.Y., Talhi, O., Jang, D., Cerella, C., Gaigneaux, A., Kim, K.W., Lee, J.W., Dicato, M., Bachari, K., Han, B.W., Silva, A.M.S., Orlikova, B., Diederich, M. (2017) Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer. Cancer letters. 416:94-108.
Abstract
Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1-targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as in vivo by zebrafish xenografts.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping