Biphasic ROS production, p53 and BIK dictate the mode of cell death in response to DNA damage in colon cancer cells.

Ozgur Kutuk,Asli Giray Kurt,Huveyda Basaga,Nurgul Aytan,Sehime Gulsun Temel,Bahriye Karakas,Ufuk Acikbas,Yi-Hsien Hsieh

doi:10.1371/journal.pone.0182809

Abstract

Necrosis, apoptosis and autophagic cell death are the main cell death pathways in multicellular organisms, all with distinct and overlapping cellular and biochemical features. DNA damage may trigger different types of cell death in cancer cells but the molecular events governing the mode of cell death remain elusive. Here we showed that increased BH3-only protein BIK levels promoted cisplatin- and UV-induced mitochondrial apoptosis and biphasic ROS production in HCT-116 wild-type cells. Nonetheless, early single peak of ROS formation along with lysosomal membrane permeabilization and cathepsin activation regulated cisplatin- and UV-induced necrosis in p53-null HCT-116 cells. Of note, necrotic cell death in p53-null HCT-116 cells did not depend on BIK, mitochondrial outer membrane permeabilization or caspase activation. These data demonstrate how cancer cells with different p53 background respond to DNA-damaging agents by integrating distinct cell signaling pathways dictating the mode of cell death.

Highlights

The mitochondrial apoptotic pathway is strictly regulated by the selective protein-protein interactions between antiapoptotic and proapoptotic BCL-2 protein family members[1]
It has been shown that BIK was largely localized in the endoplasmic reticulum (ER) and BIK-induced release of Ca2+ from the ER in augmented mitochondrial cytochrome c release occurs through Drp-1-mediated remodeling of mitochondrial cristae [5, 6, 31]
It is possible that other BH3-only proteins are involved in cisplatin- or UV-induced apoptosis in HCT-116 cells, but our results suggest that BIK binds to BCL-2 and BCL-XL to inhibit their prosurvival function following DNA damage

Summary

Introduction

The mitochondrial apoptotic pathway is strictly regulated by the selective protein-protein interactions between antiapoptotic and proapoptotic BCL-2 protein family members[1]. In response to various cellular stresses, activation of BAX and BAK by activator BH3-only proteins (BIM, BID and PUMA) coincide with the suppression of antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1) by sensitizer BH3 proteins (BAD, BIK, NOXA, BMF, HRK) and is followed by the permeabilization of the mitochondrial outer membrane. Mitochondrial outer membrane permeabilization and the release of cytochrome c into the cytosol represent the point of no return for the commitment of cell death. Cytochrome c, APAF-1 and caspase-9 form the apoptosome complex and activated caspase-9 triggers the activation of executioner caspase-3 and caspase-7 by cleaving them.

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