Stimulation of Fas/FasL-mediated apoptosis by luteolin through enhancement of histone H3 acetylation and c-Jun activation in HL-60 leukemia cells
Shih-Wei Wang
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
Search for more papers by this authorYun-Ru Chen
Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
Search for more papers by this authorJyh-Ming Chow
Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorMing-Hsien Chien
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorShun-Fa Yang
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
Search for more papers by this authorYu-Ching Wen
Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorCorresponding Author
Wei-Jiunn Lee
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Correspondence
Tsui-Hwa Tseng, Department of Medical Applied Chemistry, Chung Shan Medical University, 110 Chien-Kuo N. Road, Section 1, Taichung 402, Taiwan.
Email: [email protected]
Wei-Jiunn Lee, Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Tsui-Hwa Tseng
Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan
Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan
Correspondence
Tsui-Hwa Tseng, Department of Medical Applied Chemistry, Chung Shan Medical University, 110 Chien-Kuo N. Road, Section 1, Taichung 402, Taiwan.
Email: [email protected]
Wei-Jiunn Lee, Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.
Email: [email protected]
Search for more papers by this authorShih-Wei Wang
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
Search for more papers by this authorYun-Ru Chen
Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
Search for more papers by this authorJyh-Ming Chow
Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorMing-Hsien Chien
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorShun-Fa Yang
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
Search for more papers by this authorYu-Ching Wen
Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorCorresponding Author
Wei-Jiunn Lee
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Correspondence
Tsui-Hwa Tseng, Department of Medical Applied Chemistry, Chung Shan Medical University, 110 Chien-Kuo N. Road, Section 1, Taichung 402, Taiwan.
Email: [email protected]
Wei-Jiunn Lee, Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Tsui-Hwa Tseng
Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan
Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan
Correspondence
Tsui-Hwa Tseng, Department of Medical Applied Chemistry, Chung Shan Medical University, 110 Chien-Kuo N. Road, Section 1, Taichung 402, Taiwan.
Email: [email protected]
Wei-Jiunn Lee, Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.
Email: [email protected]
Search for more papers by this authorAbstract
Luteolin (3′,4′,5,7-tetrahydroxyflavone), which exists in fruits, vegetables, and medicinal herbs, is used in Chinese traditional medicine for treating various diseases, such as hypertension, inflammatory disorders, and cancer. However, the gene-regulatory role of luteolin in cancer prevention and therapy has not been clarified. Herein, we demonstrated that treatment with luteolin resulted in a significant decrease in the viability of human leukemia cells. In the present study, by evaluating fragmentation of DNA and poly (ADP-ribose) polymerase (PARP), we found that luteolin was able to induce PARP cleavage and nuclear fragmentation as well as an increase in the sub-G0/G1 fraction. In addition, luteolin also induced Fas and Fas ligand (FasL) expressions and subsequent activation of caspases-8 and -3, which can trigger the extrinsic apoptosis pathway, while knocking down Fas-associated protein with death domain (FADD) prevented luteolin-induced PARP cleavage. Immunoblot and chromatin immunoprecipitation (ChIP) analyses revealed that luteolin increased acetylation of histone H3, which is involved in the upregulation of Fas and FasL. Moreover, both the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways are involved in luteolin-induced histone H3 acetylation. Finally, luteolin also activated the c-Jun signaling pathway, which contributes to FasL, but not Fas, gene expression and downregulation of c-Jun expression by small interfering RNA transfection which resulted in a significant decrease in luteolin-induced PARP cleavage. Thus, our results demonstrate that luteolin induced apoptosis of HL-60 cells, and this was associated with c-Jun activation and histone H3 acetylation-mediated Fas/FasL expressions.
CONFLICTS OF INTEREST
Authors declare no conflicts of interest.
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