The Role Of ROS-mediated ERK and JNK Activation In The Induction Of Autophagy And Apoptosis In Tumour Cells By A Novel Small Molecule Compound
type: CreativeWork
description: It is now well established that chemotherapy-induced reduction in tumor load is a function of apoptotic cell death, orchestrated by intracellular caspase proteases. However, the effectiveness of some of these therapies is blunted by mutations affecting specific effectors genes controlling and/or regulating apoptotic signaling. Therefore, there has been a surge of activity around identification of novel pathways of cell death, which could function in tandem with or in the absence of efficient apoptotic machinery. In this regard, recent evidence has highlighted the existence of a novel, caspase-independent cell death pathway, termed autophagy, which is activated in response to growth factor deprivation or upon exposure to genotoxic compounds. It should be noted that autophagy has been described as a cell survival mechanism as well as a death execution pathway. Using a novel small molecule 1,3-dibutyl-2-thiooxo-imidazolidine-4,5-dione (C1), which is a strong inducer of intracellular hydrogen peroxide (H2O2), this work demonstrated the simultaneous induction of non-canonical autophagy and apoptotic cell death in human colorectal carcinoma cells. It was later discovered that the ability of C1 to induce autophagy is not limited to a single cell line. Of importance, this study supported the existence of non-canonical autophagy induced by C1. Whereas, silencing of the integral mediator of autophagy, beclin1 did not provide protection against autophagy or cell death, Atg 7 or Ulk1 knock-down significantly abrogated C1-induced autophagy. In the current study, the induction of autophagy and apoptosis was found to be mutually exclusive. Despite this fact, early H2O2 production was critical in controlling the induction of autophagy and apoptosis via activation of extracellular regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Inhibition of ERK and JNK virtually completely blocked drug-induced autophagy and apoptosis. Interestingly, inhibition of JNK activity reversed C1-…
abstract: It is now well established that chemotherapy-induced reduction in tumor load is a function of apoptotic cell death, orchestrated by intracellular caspase proteases. However, the effectiveness of some of these therapies is blunted by mutations affecting specific effectors genes controlling and/or regulating apoptotic signaling. Therefore, there has been a surge of activity around identification of novel pathways of cell death, which could function in tandem with or in the absence of efficient apoptotic machinery. In this regard, recent evidence has highlighted the existence of a novel, caspase-independent cell death pathway, termed autophagy, which is activated in response to growth factor deprivation or upon exposure to genotoxic compounds. It should be noted that autophagy has been described as a cell survival mechanism as well as a death execution pathway. Using a novel small molecule 1,3-dibutyl-2-thiooxo-imidazolidine-4,5-dione (C1), which is a strong inducer of intracellular hydrogen peroxide (H2O2), this work demonstrated the simultaneous induction of non-canonical autophagy and apoptotic cell death in human colorectal carcinoma cells. It was later discovered that the ability of C1 to induce autophagy is not limited to a single cell line. Of importance, this study supported the existence of non-canonical autophagy induced by C1. Whereas, silencing of the integral mediator of autophagy, beclin1 did not provide protection against autophagy or cell death, Atg 7 or Ulk1 knock-down significantly abrogated C1-induced autophagy. In the current study, the induction of autophagy and apoptosis was found to be mutually exclusive. Despite this fact, early H2O2 production was critical in controlling the induction of autophagy and apoptosis via activation of extracellular regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Inhibition of ERK and JNK virtually completely blocked drug-induced autophagy and apoptosis. Interestingly, inhibition of JNK activity reversed C1-…
author: WONG CHEW HOOI
keywords: ROS, Autophagy, Apoptosis, ERK, JNK, Cell Death
date published: 2009-08-20
date modified: 2026-07-24T03:32:30Z
provider: National University of Singapore
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: National University of Singapore