Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells
The present study demonstrated that 2′-hydroxycinnamaldehyde (2′-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expres...
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MDPI AG
2021-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/11/1794 |
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| author | Kyung-Sook Chung Chae-Bin Yoo Jeong-Hun Lee Hwi-Ho Lee Sang-Eun Park Hee-Soo Han Su-Yeon Lee Byoung-Mok Kwon Jung-Hye Choi Kyung-Tae Lee |
| author_facet | Kyung-Sook Chung Chae-Bin Yoo Jeong-Hun Lee Hwi-Ho Lee Sang-Eun Park Hee-Soo Han Su-Yeon Lee Byoung-Mok Kwon Jung-Hye Choi Kyung-Tae Lee |
| author_sort | Kyung-Sook Chung |
| collection | DOAJ |
| description | The present study demonstrated that 2′-hydroxycinnamaldehyde (2′-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expression, (3) cytochrome <i>c</i> release into the cytosol, (4) loss of mitochondrial membrane potential (Δ<i>Ψ<sub>m</sub></i>), and (5) caspase activation. 2′-HCA also induced the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase1/2 (ERK1/2) in HL-60 cells. The pharmacological and genetic inhibition of JNK effectively prevented 2′-HCA-induced apoptosis and activator protein-1 (AP-1)-DNA binding. In addition, 2′-HCA resulted in the accumulation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH) and protein thiols (PSH) in HL-60 cells. NAC treatment abrogated 2′-HCA-induced JNK phosphorylation, AP-1-DNA binding, and Bim mitochondrial translocation, suggesting that oxidative stress may be required for 2′-HCA-induced intrinsic apoptosis. Xenograft mice inoculated with HL-60 leukemia cells demonstrated that the intraperitoneal administration of 2′-HCA inhibited tumor growth by increasing of TUNEL staining, the expression levels of nitrotyrosine and pro-apoptotic proteins, but reducing of PCNA protein expression. Taken together, our findings suggest that 2′-HCA induces apoptosis via the ROS-dependent JNK pathway and could be considered as a potential therapeutic agent for leukemia. |
| first_indexed | 2024-03-10T05:09:32Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T05:09:32Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-fe677e391a9f4ab097880eb97737028d2023-11-23T00:57:43ZengMDPI AGPharmaceutics1999-49232021-10-011311179410.3390/pharmaceutics13111794Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia CellsKyung-Sook Chung0Chae-Bin Yoo1Jeong-Hun Lee2Hwi-Ho Lee3Sang-Eun Park4Hee-Soo Han5Su-Yeon Lee6Byoung-Mok Kwon7Jung-Hye Choi8Kyung-Tae Lee9Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaLaboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, KoreaThe present study demonstrated that 2′-hydroxycinnamaldehyde (2′-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expression, (3) cytochrome <i>c</i> release into the cytosol, (4) loss of mitochondrial membrane potential (Δ<i>Ψ<sub>m</sub></i>), and (5) caspase activation. 2′-HCA also induced the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase1/2 (ERK1/2) in HL-60 cells. The pharmacological and genetic inhibition of JNK effectively prevented 2′-HCA-induced apoptosis and activator protein-1 (AP-1)-DNA binding. In addition, 2′-HCA resulted in the accumulation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH) and protein thiols (PSH) in HL-60 cells. NAC treatment abrogated 2′-HCA-induced JNK phosphorylation, AP-1-DNA binding, and Bim mitochondrial translocation, suggesting that oxidative stress may be required for 2′-HCA-induced intrinsic apoptosis. Xenograft mice inoculated with HL-60 leukemia cells demonstrated that the intraperitoneal administration of 2′-HCA inhibited tumor growth by increasing of TUNEL staining, the expression levels of nitrotyrosine and pro-apoptotic proteins, but reducing of PCNA protein expression. Taken together, our findings suggest that 2′-HCA induces apoptosis via the ROS-dependent JNK pathway and could be considered as a potential therapeutic agent for leukemia.https://www.mdpi.com/1999-4923/13/11/17942′-hydroxycinnamaldehydereactive oxygen species (ROS)Bim |
| spellingShingle | Kyung-Sook Chung Chae-Bin Yoo Jeong-Hun Lee Hwi-Ho Lee Sang-Eun Park Hee-Soo Han Su-Yeon Lee Byoung-Mok Kwon Jung-Hye Choi Kyung-Tae Lee Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells Pharmaceutics 2′-hydroxycinnamaldehyde reactive oxygen species (ROS) Bim |
| title | Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells |
| title_full | Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells |
| title_fullStr | Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells |
| title_full_unstemmed | Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells |
| title_short | Regulation of ROS-Dependent JNK Pathway by 2’-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells |
| title_sort | regulation of ros dependent jnk pathway by 2 hydroxycinnamaldehyde inducing apoptosis in human promyelocytic hl 60 leukemia cells |
| topic | 2′-hydroxycinnamaldehyde reactive oxygen species (ROS) Bim |
| url | https://www.mdpi.com/1999-4923/13/11/1794 |
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