The BFL1 protein, also known as A1, is part of the Bcl-2 family of proteins found in human cells. This family regulates cell survival and programmed cell death, a process called apoptosis. BFL1 primarily acts as an anti-apoptotic regulator, preventing cells from undergoing self-destruction.
Fundamental Role in Cell Survival
Under normal conditions, BFL1 helps maintain cellular balance by inhibiting programmed cell death. It is located at the outer mitochondrial membrane, where it helps regulate voltage-dependent anion channels (VDACs). VDACs influence mitochondrial membrane potential and the release of factors that can trigger apoptosis.
BFL1 functions by interacting with pro-apoptotic proteins like Bak and tBid, which initiate cell death. By binding to these proteins, BFL1 neutralizes their activity, preventing them from forming pores in the mitochondrial membrane. This keeps the mitochondrial membrane intact, preventing the release of factors that would lead to cell dismantling. The balance between pro- and anti-apoptotic Bcl-2 family proteins, including BFL1, determines cell survival or apoptosis.
Connection to Cancer Development
BFL1’s normal function of inhibiting cell death can become dysregulated in cancer, contributing to uncontrolled cell growth and tumor survival. Overexpression of BFL1 allows cancer cells to evade apoptosis, a key mechanism by which the body removes damaged or abnormal cells. This evasion can lead to sustained proliferation of malignant cells and resistance to various cancer treatments, including chemotherapy.
BFL1 overexpression has been observed in a range of human cancers. For instance, it has been implicated in certain blood cancers, such as acute myeloid leukemia (AML), where its co-expression with Wilms Tumour protein (WT1) is linked to poor patient outcomes. BFL1 also contributes to the survival of acute promyelocytic leukemia cells, particularly those treated with all-trans retinoic acid (ATRA) therapy. In solid tumors, BFL1 has been found to be relevant in melanoma, where its amplification is associated with reduced sensitivity to BRAF inhibitors. The ability of BFL1 to block cell death even in the presence of other targeted therapies highlights its role in promoting tumor resilience.
Targeting for New Therapies
Understanding BFL1’s role in cancer cell survival has opened avenues for developing new therapeutic strategies. The concept behind targeting BFL1 is to inhibit its anti-apoptotic activity, thereby making cancer cells more susceptible to programmed cell death or to existing anti-cancer treatments. Researchers are exploring various approaches to modulate BFL1 activity, aiming to restore the cell’s natural ability to eliminate cancerous cells.
One promising strategy involves the development of small molecule inhibitors designed to directly block BFL1’s function. While no effective BFL1 inhibitors are currently available in clinical use, research is ongoing to identify and refine such compounds. Another area of investigation involves understanding how BFL1 contributes to resistance to other targeted therapies, such as BH3-mimetics, which are drugs designed to mimic pro-apoptotic proteins. Inhibiting BFL1 could potentially overcome this resistance, allowing existing therapies to be more effective. The fact that deletion of the mouse equivalent of BFL1, called A1, has minimal impact on animal well-being suggests that targeting BFL1 may result in limited side effects, making it an attractive target for future cancer treatments.