Fisetin Induces Apoptosis of HSC3 Human Oral Cancer Cells Through Endoplasmic Reticulum Stress and Dysfunction of Mitochondria-mediated Signaling Pathways.

Abstract

BACKGROUND/AIM:

Oral cancer has been reported to be one of the major cancer-related diseases in human populations and the treatment of oral cancer is still unsatisfied. Fisetin, is a flavonoid from plants and has several biological activities such as antioxidant, anti-inflammatory and anticancer function, but its cytotoxicity in human oral cancer cells is unknown. In the present study, we investigated fisetin-induced cytotoxic effects on HSC3 human oral cancer cells in vitro. Materials and Methods/Results: We used flow cytometric assay to show fisetin induced apoptotic cell death through increased reactive oxygen species and Ca2+, but reduced the mitochondrial membrane potential and increased caspase-8, -9 and -3 activities in HSC3 cells. Furthermore, we also used 4' 6-diamidino-2-phenylindole staining to show that fisetin induced chromatin condensation (apoptotic cell death), and Comet assay to show that fisetin induced DNA damage in HSC3 cells. Western blotting was used to examine the levels of apoptotic-associated protein and results indicated that fisetin increased expression of pro-apoptotic proteins such as B-cell lymphoma 2 (BCL2) antagonist/killer (BAK) and BCL2-associated X (BAX) but reduced that of anti-apoptotic protein such as BCL2 and BCL-x, and increased the cleaved forms of caspase-3, -8 and -9, and cytochrome c, apoptosis-inducing factor (AIF) and endonuclease G (ENDO G) in HSC3 cells. Confocal microscopy showed that fisetin increased the release of cytochrome c, AIF and ENDO G from mitochondria into the cytoplasm.

CONCLUSION:

Based on these observations, we suggest that fisetin induces apoptotic cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways.

• Authors: Yung-Luen Shih, Fang-Ming Hung, Ching-Hsiao Lee, Ming-Yang Yeh, Mei-Hui Lee, Hsu-Feng Lu, Yung-Liang Chen, Jia-You Liu, Jing-Gung Chung
• Journal: In vivo (Athens, Greece) (In Vivo) 2017 Nov-Dec Vol. 31 Issue 6 Pg. 1103-1114 ISSN: 1791-7549 [Electronic] Greece
• PMID: 29102932 (Publication Type: Journal Article)
• Copyright: Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Flavonoids
• Flavonols
• Neoplasm Proteins
• Reactive Oxygen Species
• Caspases
• fisetin

Topics

• Apoptosis (drug effects)
• Caspases (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Flavonoids (administration & dosage)
• Flavonols
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, pathology)
• Mouth Neoplasms (drug therapy, genetics, pathology)
• Neoplasm Proteins (genetics)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)