Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species

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.

Keywords: Bcl-2 family; cancer invasion and metastasis; mitochondrial respiration; reactive oxygen species.

Figure 1. Regulation of cell migration and invasion by pro-survival Bcl-2 family members

Up-regulation of pro-survival Bcl-2 family members results in stimulation of diverse sets of signaling components such as kinases, transcription factors, cell surface receptors, and matrix-degrading enzymes, leading to promotion of cell migration and invasion. The hierarchical relationship and importance of each signaling component may vary depending on the experimental conditions.

Figure 2. Regulation of complex-I-dependent ROS production by Bcl-2 family proteins

A. Bax residing in the outer mitochondrial membrane in its tail-anchored form protrudes the four residues in its C-terminus (KKMG) into the intermembrane space. This topology allows the interaction of the C-terminal tail with subunits of complex-I in the inner mitochondrial membrane. ND5 is one such subunit that participates in the interaction. As a result of the interaction, the enzymatic activity and ROS-producing ability of complex-I are suppressed. Although not depicted here, Bak in the outer mitochondrial membrane also interacts with ND5 through its four C-terminal residues (FFKS). B. The interactions between Bax/Bak and complex-I are disrupted when Bcl-w and Bcl-X_L bind to Bax and Bak. Consequently, the inhibitory effects of Bax and Bak on complex-I are relieved, increasing complex-I activity and ROS production. C. Subunits of complex-I, particularly ND5, are frequently mutated in cancer. One such natural mutation of ND5 (ND5^G13289A) prevents its interaction with Bax, promoting complex-I activity and ROS production. ROS generated by mutations in complex-I or the actions of pro-survival Bcl-2 family members then stimulate diverse signaling pathways, leading to the promotion of cancer cell migration, invasion, and metastasis.

Figure 3. Bcl-2 proteins may regulate cell migration and invasion by binding to multiple targets

In addition to the role of complex-I in cell migration and invasion, Bcl-2 has been reported to bind to Twist and COX Va, a subunit of complex-IV. Myosin Va was also shown to bind to Bcl-X_L. Given the ability of Bcl-2 to facilitate the production of respiratory ROS, the ability of Twist to promote epithelial-mesenchymal transition and cell invasion, and the ability of myosin Va to regulate cell motility, such interactions may contribute to the pro-invasive activity of Bcl-2 and Bcl-X_L. However, these possibilities have not been examined directly.