RETRACTED ARTICLE: ICB3E induces iNOS expression by ROS-dependent JNK and ERK activation for apoptosis of leukemic cells

Abstract

The role of c-Jun N terminal Kinase (JNK) has been well documented in various cellular stresses where it leads to cell death. Similarly, extracellular signal-regulated kinase (ERK) which was identified as a signalling molecule for survival pathway has been shown recently to be involved in apoptosis also. Recently we reported that ICB3E, a synthetic analogue of Piper betle leaf-derived apoptosis-inducing agent hydroxychavicol (HCH), possesses anti-chronic myeloid leukemia (CML) acitivity in vitro and in vivo without insight on mechanism of action. Here we report that ICB3E is three to four times more potent than HCH in inducing apoptosis of leukemic cells without having appreciable effects on normal human peripheral blood mononuclear cells, mouse fibroblast cell line NIH3T3 and monkey kidney epithelial cell line Vero. ICB3E causes early accumulation of mitochondria-derived reactive oxygen species (ROS) in K562 cells. Unlike HCH, ICB3E treatment caused ROS dependent activation of both JNK, ERK and induced the expression of iNOS leading to generation of nitric oxide (NO). This causes cleavage of caspase 9, 3 and PARP leading to apoptosis. Lack of cleavage of caspase 8 and inability of blocking chimera antibody to DR5 or neutralizing antibody to Fas to reverse ICB3E-mediated apoptosis suggest the involvement of only intrinsic pathway. Our data reveal a novel ROS-dependent JNK/ERK-mediated iNOS activation pathway which leads to NO mediated cell death by ICB3E.

Effects of nitrite exposure on haematological parameters, oxidative stress and apoptosis in juvenile turbot (Scophthalmus maximus)

“…Numerous studies indicated that ERK1/2 and JUK could be activated by many environmental stressors or chemical agents via induction of oxidative stress, but this phenomenon was inhibited by treatment with antioxidants Geng et al, 2014;Wang et al, 2014;Zhang et al, 2012). Also, oxidative stress could increase the protein or mRNA levels of MAPKs (Biswas et al, 2012;Liu et al, 2012;Liu et al, 2013). Our study showed that exposure to nitrite increased the mRNA levels of JUK1, implying that the JUK signaling pathways likely played a role in the damage of the turbot gill or branchial cells after nitrite exposure.…”

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

“…23,24 While ERK signaling tends to promote cell migration and metastasis, along with cell survival mechanisms, 25 more recent reports have also shown that this kinase can mediate breast cancer cell death. 26–28 …”

Additive Effects of Nicotine and High-Fat Diet on Hepatocellular Apoptosis in Mice: Involvement of Caspase 2 and Inducible Nitric Oxide Synthase-Mediated Intrinsic Pathway Signaling

“…Of importance, oxidative stress can trigger caspase 2 activation [18, 20, 21]. Nitric oxide (NO) production through up-regulation of inducible nitric oxide synthase (iNOS) can also be a potential target of JNK signaling [22, 23]. Increased nitric oxide (NO) production, through upregulation of iNOS, has also been implicated in cellular injury and apoptosis in a variety of cell systems, including hepatocytes [22, 23, 24].…”

“…Nitric oxide (NO) production through up-regulation of inducible nitric oxide synthase (iNOS) can also be a potential target of JNK signaling [22, 23]. Increased nitric oxide (NO) production, through upregulation of iNOS, has also been implicated in cellular injury and apoptosis in a variety of cell systems, including hepatocytes [22, 23, 24]. One possible mechanism by which NO can induce apoptosis is through perturbation of the BAX/BCL2 rheostat and the subsequent activation of the mitochondria-dependent death pathway [22, 24].…”