The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells

Zhenzhen Zhang, Chao Zhang, Ye Ding, Qian Zhao, Lifang Yang, Jingjing Ling, Ling Liu, Hui Ji, Yihua Zhang

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

In this study, we describe that a novel synthesized compound, olean-28,13β-olide 2 (OLO-2), exhibits selective cytotoxic activity via inducing apoptosis in human hepatocellular carcinoma (HCC) cell lines but not normal human hepatic cells in vitro. Exposure of human HCC HepG2 cells to OLO-2 results in significant loss of mitochondrial transmembrane potential (δ. Ψm), the release of cytochrome c, the recruitment of B-cell lymphoma 2 (Bcl-2) assaciated X protein (Bax) and the downregulation of Bcl-2. The apoptosis induced by OLO-2 is associated with the activation of caspase-3/9 and the nuclear translocation of apoptosis inducing factor (AIF). Moreover, the increase of phosphorylated p38 and c-Jun N-terminal kinase (JNK) is observed. OLO-2-induced the externalization of phosphatidyl-serine (PS) and the loss of δ. Ψm are blocked by p38 inhibitor SB203580 or JNK inhibitor SP600125. In addition, OLO-2 provokes the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine (NAC) almost completely blocks OLO-2-induced apoptosis and the activation of p38 and JNK. Taken together, the present study demonstrates that OLO-2 exhibits its cytotoxic activity through intrinsic apoptosis via ROS generation and the activation of p38 and JNK. Its potential to be a candidate of anti-cancer agent is worth being further investigated.

Original languageEnglish (US)
Pages (from-to)38-47
Number of pages10
JournalFood and Chemical Toxicology
Volume63
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

hepatoma
reactive oxygen species
Hepatocellular Carcinoma
Reactive Oxygen Species
phosphotransferases (kinases)
Phosphotransferases
apoptosis
Chemical activation
Cells
Apoptosis
Hep G2 Cells
B-Cell Lymphoma
lymphoma
Acetylcysteine
B-lymphocytes
cells
Apoptosis Inducing Factor
Caspase 9
JNK Mitogen-Activated Protein Kinases
Phosphatidylserines

Keywords

  • Apoptosis
  • Cytotoxic
  • Human HCC cells
  • Mitochondria
  • OLO-2

ASJC Scopus subject areas

  • Food Science
  • Toxicology

Cite this

The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells. / Zhang, Zhenzhen; Zhang, Chao; Ding, Ye; Zhao, Qian; Yang, Lifang; Ling, Jingjing; Liu, Ling; Ji, Hui; Zhang, Yihua.

In: Food and Chemical Toxicology, Vol. 63, 2014, p. 38-47.

Research output: Contribution to journalArticle

Zhang, Zhenzhen ; Zhang, Chao ; Ding, Ye ; Zhao, Qian ; Yang, Lifang ; Ling, Jingjing ; Liu, Ling ; Ji, Hui ; Zhang, Yihua. / The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells. In: Food and Chemical Toxicology. 2014 ; Vol. 63. pp. 38-47.
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T1 - The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells

AU - Zhang, Zhenzhen

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AU - Yang, Lifang

AU - Ling, Jingjing

AU - Liu, Ling

AU - Ji, Hui

AU - Zhang, Yihua

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AB - In this study, we describe that a novel synthesized compound, olean-28,13β-olide 2 (OLO-2), exhibits selective cytotoxic activity via inducing apoptosis in human hepatocellular carcinoma (HCC) cell lines but not normal human hepatic cells in vitro. Exposure of human HCC HepG2 cells to OLO-2 results in significant loss of mitochondrial transmembrane potential (δ. Ψm), the release of cytochrome c, the recruitment of B-cell lymphoma 2 (Bcl-2) assaciated X protein (Bax) and the downregulation of Bcl-2. The apoptosis induced by OLO-2 is associated with the activation of caspase-3/9 and the nuclear translocation of apoptosis inducing factor (AIF). Moreover, the increase of phosphorylated p38 and c-Jun N-terminal kinase (JNK) is observed. OLO-2-induced the externalization of phosphatidyl-serine (PS) and the loss of δ. Ψm are blocked by p38 inhibitor SB203580 or JNK inhibitor SP600125. In addition, OLO-2 provokes the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine (NAC) almost completely blocks OLO-2-induced apoptosis and the activation of p38 and JNK. Taken together, the present study demonstrates that OLO-2 exhibits its cytotoxic activity through intrinsic apoptosis via ROS generation and the activation of p38 and JNK. Its potential to be a candidate of anti-cancer agent is worth being further investigated.

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