Abstract
Although Bcl-2 family proteins were originally identified as key regulators of apoptosis, an impressive body of evidence has shown that pro-survival members of the Bcl-2 family, including Bcl-2, Bcl-XL, and Bcl-w, can also promote cell migration, invasion, and cancer metastasis. Interestingly, cell invasion was recently found to be suppressed by multidomain pro-apoptotic members of the Bcl-2 family, such as Bax and Bak. While the mechanisms underlying these new functions of Bcl-2 proteins are just beginning to be studied, reactive oxygen species (ROS) have emerged as inducers of cell invasion and the production of ROS from mitochondrial respiration is known to be promoted and suppressed by the pro-survival and multidomain pro-apoptotic Bcl-2 family members, respectively. Here, I review the evidence supporting the ability of Bcl-2 proteins to regulate cancer cell invasion and metastasis, and discuss our current understanding of their underlying mechanisms, with a particular focus on mitochondrial respiration and ROS, which could have implications for the development of strategies to overcome tumor progression.
Highlights
Bcl-2 family proteins are key regulators of cell death that can either suppress or promote apoptosis [1,2,3]
Inhibition of reactive oxygen species (ROS) induction using antioxidants or metabolic inhibitors prevents the ability of Bcl-w and Bcl-XL to stimulate phosphoinositide 3-kinase (PI3K)/Akt/MMP2-dependent invasion pathways and promote cell invasion [22, 25], suggesting that these functions of pro-survival Bcl-2 family members can be mediated by ROS
Consistent with this, the knockdown of Bax and Bak in lung cancer cells increases complex-I activity, Ψm, and ATP levels [25]. All of these studies support the ability of multidomain pro-apoptotic members to inhibit mitochondrial respiration. These findings suggest that multidomain pro-apoptotic members suppress ROS production by inhibiting mitochondrial respiration, which is further supported by the ability of rotenone to prevent increases in ROS levels induced by Bax knockdown [25]
Summary
Bcl-2 family proteins are key regulators of cell death that can either suppress or promote apoptosis [1,2,3]. Consistent with this pro-invasive activity, studies using mouse models have shown that pro-survival members of the Bcl-2 family can promote tumor metastasis.
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