Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer

• Published in: Cancer letters Vol. 416; pp. 94 - 108
• Main Authors: Lee, Jin-Young, Talhi, Oualid, Jang, Dongman, Cerella, Claudia, Gaigneaux, Anthoula, Kim, Kyu-Won, Lee, Jung Weon, Dicato, Mario, Bachari, Khaldoun, Han, Byung Woo, Silva, Artur M.S., Orlikova, Barbora, Diederich, Marc
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2018; Elsevier Limited
• Subjects: Acidification; Aldehyde dehydrogenase; Anticoagulants; Antioxidants; Apoptosis; Bcl-x protein; BH3 mimetics; Cancer therapies; Cell cycle; Cell death; Cell proliferation; Chemotherapy; Computer applications; Coumarin; Cytokines; Deoxyribonucleic acid; DNA; Docking; Endoplasmic reticulum; Golgi apparatus; Growth factors; Homeostasis; Immunogenic cell death; Immunogenicity; Inflammation; Inhibitor drugs; K-Ras protein; Kinases; KRAS mutation; Lung cancer; Mcl-1 protein; Mutation; Non-small cell lung cancer; Non-small cell lung carcinoma; Proteins; Respiration; Rodents; Senescence; STAT3; Stat3 protein; Stress analysis; Stress response; Xenografts; KRAS mutation; Coumarin; BH3 mimetics; Immunogenic cell death; Non-small cell lung cancer; STAT3
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.12.007

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.