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.

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

“…By preventing each of the p53/ p21, p53/Bcl-w, or p21/Bcl-w interactions by mutation or deletion, we further showed that all three interactions are required to form the p53/p21/Bcl-w complex and that only the trimeric complex, but not any of the individual dimers, facilitates the release of Bax from Bcl-w. We also analyzed the ability of p53 K305N , which we used as a model for cytoplasmic p53, to form a complex with p21 and Bcl-w and to liberate Bax and did not find a noticeable difference from the results obtained with p53 wt . Liberated Bax promotes apoptosis or suppresses healthy cell invasion (4)(5)(6)(7)(8). We found that cytoplasmic p53 and p21 are both required to manifest these anti-invasive and proapoptotic activities.…”

“…In nonapoptotic cells, Bcl-2 proteins regulate cell migration and invasion, and thus, cancer metastasis (6). These features are promoted by Bcl-2, Bcl-X L , and Bcl-w and suppressed by Bax and Bak.…”

“…These features are promoted by Bcl-2, Bcl-X L , and Bcl-w and suppressed by Bax and Bak. Bax and Bak reduce the ability of mitochondria to produce reactive oxygen species (ROS), key inducers of cell invasion and cancer metastasis, whereas Bcl-w and Bcl-X L promote ROS production by binding to and inhibiting Bax and Bak (6)(7)(8). Notably, p53 and its mutant derivatives (e.g., p53 K305N ) frequently accumulate in the cytoplasm and mitochondria of normal and cancer cells even without apoptotic stimulation (9,10), suggesting the existence of cytoplasmic/mitochondrial functions of p53 in healthy cells.…”

A Systematic Review of the Immune-Regulating and Anticancer Activities of Pseudolaric Acid B

“…The ratio of Bcl-2/Bax takes on a higher level in cancer cells compared with the original cells (Um, 2016). Up-regulation of Bax and down-regulation of Bcl-2 could facilitate apoptosis in various cancer cells of different origins.…”

“…ROS was crucial for maintaining normal physiological functions during the development of cell cycle progression, proliferation and cell death (Um, 2016). PAB has evident effects on the increase of the level of ROS (Zhao et al, 2012; Liu et al, 2013; Qi et al, 2013a,b).…”