Abstract
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.
Highlights
Bcl-2 family members are among the most important pro-oncogenic proteins in all forms of cancer [1, 2]
We demonstrate that Mcl-1-regulated chemotherapy-induced senescence (CIS) requires reactive oxygen species (ROS), but mitochondrial ROS, and that these events are upstream of activation of the DNA damage response, another necessary step toward senescence
To better understand how Mcl-1 regulates chemotherapy-induced senescence, we started by examining a well-known component of this process, the activation of the DNA damage response (DDR), [14] Previous studies have demonstrated that Mcl-1 regulates and prevents DNA damage directly at the site of DNA breaks during apoptosis, as evidenced by coimmuno-precipitation of Mcl-1 with molecules such as γ-H2AX [15]
Summary
Bcl-2 family members are among the most important pro-oncogenic proteins in all forms of cancer [1, 2]. Most studies suggest unique physical characteristics of the Mcl-1 anti-apoptotic binding cleft account for this difficulty in targeting [8]. We recently showed that Mcl-1 contains an additional unique domain that is distinct among Bcl-2 family members and critical for its known ability to inhibit chemotherapy-induced senescence (but not apoptosis) [9, 10]. This observation may explain why current targeted therapies do not completely inhibit Mcl-1 activity, as they do not account for this domain. Much of Mcl-1’s non-apoptotic, anti-senescence activities remain poorly understood
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