Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

• Published in: Oncotarget 2017-04, Vol.8 (17), p.28154-28168
• Main Authors: Demelash, Abeba, Pfannenstiel, Lukas W, Liu, Li, Gastman, Brian R
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antioxidants - metabolism; Cell Line, Tumor; Cellular Senescence - drug effects; Cellular Senescence - genetics; DNA Damage; Gene Expression Regulation; Humans; Mitochondria - drug effects; Mitochondria - metabolism; Myeloid Cell Leukemia Sequence 1 Protein - chemistry; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Protein Binding; Protein Interaction Domains and Motifs; Reactive Oxygen Species - metabolism; Research Paper
• ISSN: 1949-2553
• DOI: 10.18632/oncotarget.15962

Mcl-1, a Bcl-2 family member, is highly expressed in a variety of human cancers and is believed to enhance tumorigenic potential and chemotherapy resistance through the inhibition of apoptosis and senescence. We previously reported that Mcl-1's regulation of chemotherapy-induced senescence (CIS) is dependent on its ability to prevent reactive oxygen species (ROS) generation. In this report, we demonstrate that Mcl-1-regulated CIS requires not only ROS, but specifically mitochondrial ROS, and that these events are upstream of activation of the DNA damage response, another necessary step toward senescence. Mcl-1's anti-senescence activity also involves the unique ability to inhibit ROS formation by preventing the upregulation of pro-oxidants. Specifically, we found that NADPH oxidases (NOXs) are regulated by Mcl-1 and that NOX4 expression in particular is a required step for CIS induction that is blocked by Mcl-1. Lastly, we illustrate that by preventing expression of NOX4, Mcl-1 limits its availability in the mitochondria, thereby lowering the production of mitochondrial ROS during CIS. Our studies not only define the essential role of Mcl-1 in chemoresistance, but also for the first time link a key pro-survival Bcl-2 family member with the NOX protein family, both of which have significant ramifications in cancer progression.