Targeting the mitochondria activates two independent cell death pathways in the ovarian cancer stem cells
Menée in vitro, cette étude montre qu'un dérivé d'isoflavone agit, par deux voies de signalisation de mort cellulaire, sur les mitochondries des cellules souches cancéreuses de l'ovaire
Cancer stem cells are responsible for tumor initiation and chemo-resistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells (OCSCs) are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the OCSCs are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of OCSCs. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of "cellular starvation" that activates two independent pathways: 1) AMPKα1 pathway leading to mTOR inhibition; and 2) mitochondrial MEK/ERK pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemo-resistant cell population opens a new venue for treating ovarian cancer patients.
http://mct.aacrjournals.org/content/early/2011/06/15/1535-7163.MCT-11-0023.abstract