Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence
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Abeba Demelash1, Lukas W. Pfannenstiel1, Li Liu1, Brian R. Gastman1,2
1Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
2Institutes of Head and Neck, Dermatology and Plastic Surgery, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
Brian R. Gastman, email: email@example.com
Keywords: senescence, cancer therapy, Mcl-1, reactive oxygen species, NOX4
Received: December 21, 2016 Accepted: February 27, 2017 Published: March 07, 2017
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.
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