Explore BCL-2

The BCL-2 family of proteins and its role in apoptosis

The BCL-2 family of proteins is known as an important gatekeeper to the apoptotic response. This group of structurally related proteins comprises pro-apoptotic and anti-apoptotic members (Figure 2.1) that interact with one another.⁵

Short sequences of amino acids common to BCL-2 and other members of this protein family are known as BCL-2 homology (BH) motifs.⁵ At least 1 BH motif is contained in each of the BCL-2 family members. These motifs, in part, contribute to the function of each member.^5,6

The BCL-2 family members can be classified into 3 functional groups: anti-apoptotic proteins such as BCL-2, pro-apoptotic effectors, and pro-apoptotic activators (Figure 2.1). Preclinical data suggest that activators, which contain only a single BH3 motif, are important mediators in the cellular response to stresses such as DNA damage.⁶

Effectors are those BCL-2 proteins closely associated with the mitochondrial membrane, and when stimulated by BH3-only activators, promote the formation of pores in the mitochondrial membrane, initiating the apoptotic program.^7,8

Figure 2.1 The BCL-2 family^5,6

Apoptosis-promoting effects from both effectors and activators are inhibited by direct interaction with anti-apoptotic BCL-2 family members.⁹ In preclinical models, BCL-2 binds and sequesters BH3-only activators and prevents them from interacting with the pore-forming effectors. Likewise, BCL-2 can directly influence effectors to prevent mitochondrial pore formation (Figure 2.2). The dynamic balance that occurs between anti-apoptotic members, such as BCL-2, and pro-apoptotic members helps determine whether the cell initiates apoptosis.^6,7

Figure 2.2 Functional role of BCL-2^6,7

Tumor cells may become dependent on BCL-2 for survival

Similar to oncogene addiction, in which tumor cells rely on a single dominant gene for survival, tumor cells may also become dependent on BCL-2 in order to survive.⁵ In response to stress signals, malignant cells may express pro-apoptotic activators. Some cancer cells overexpress BCL-2,¹ which can dampen this pro-apoptotic response. The result is in many cases an abundance of pro-apoptotic activators bound and sequestered by BCL-2. In this scenario, cancer cells are thought to be “primed” for apoptosis, in that they may contain sufficient amounts of the pro-apoptotic activators, if displaced from BCL-2, to induce programmed cell death (Figure 3.1). Cancers that depend on BCL-2 for survival in this way are likely to be sensitive to BCL-2 modulation.¹⁰

Figure 3.1 Cell priming¹⁰

BCL-2 expression in disease

The dynamic role of pro- and anti-apoptotic proteins, among other proteins, may alter the significance of increased BCL-2 expression in human disease. However, the wide variety of cancer types associated with aberrant expression of BCL-2 is consistent with its role as an apoptotic regulator (Table 3.2).¹⁰

BCL-2 expression in leukemia

Less than 5% of patients with chronic lymphocytic leukemia harbor a detectable BCL-2 gene rearrangement, although the vast majority overexpress BCL-2.¹¹ Increased expression of BCL-2 is also found frequently in acute myeloid leukemia¹² and in nearly all patients with acute lymphocytic leukemia.¹²

BCL-2 expression in non-Hodgkin lymphoma

In follicular lymphoma, an estimated 90% of patients harbor a t(14;18) chromosomal translocation in tumor cells,^13,14 which is thought to cause overexpression of BCL-2 protein.¹⁵ More than 40% of diffuse large B-cell lymphoma patients were categorized as having relatively high BCL-2 expression.¹⁶

BCL-2 expression in solid tumors

BCL-2 may also play a role in nonhematologic tumors, and inappropriate expression has been observed in solid tumors such as prostate, breast, and small cell and non-small cell lung cancers.^17-20 In small cell lung cancer, high BCL-2 expression in >90% of patients has been reported.¹⁹ Ovarian, neuroblastoma, bladder, colorectal, and some head and neck cancers have all exhibited significant levels of BCL-2 expression.^21-25

Table 3.2 Select clinical evidence in cancer

Cell priming

Cellular stresses endured by nearly all cancer cells—limited blood supply, reactive oxygen species, and exposure to chemotoxins—can lead to increases in pro-apoptotic proteins, much like they would in normal cells. When BCL-2 is overexpressed in cancer cells, it may inhibit the pro-apoptotic signals, allowing the cancer cell to survive under stressful conditions. The high levels of pro-apoptotic proteins bound and sequestered by increased BCL-2 may result in what is called a primed state (Figure 4.1). Primed cells are thought to have a high apoptotic potential: in other words, displacement of pro-apoptotic proteins from BCL-2 can result in a large enough increase in free pro-apoptotic proteins to initiate apoptosis.⁶

The primed state provides a strong rationale for conducting research related to the targeting and inhibition of BCL-2.

Ongoing BCL-2 research

Many anticancer approaches have shown to elicit their effects via apoptosis,^3,29,30 in which BCL-2 might play a significant role. Some preclinical models suggested that inhibition of BCL-2 may potentiate the effect of conventional chemotoxic agents,^31,32 warranting further study in a clinical setting. In preclinical models, overexpression of anti-apoptotic BCL-2 family members rendered cancer cells resistant to multiple classes of anticancer drugs, including DNA-damaging and antimicrotubule agents,³³ nucleoside analogs,³³ glucocorticoids,³⁴ and immunotherapy.³⁴ Further study of the role of BCL-2 in acquired resistance to cancer therapy is required to substantiate these results.

Figure 4.1 Cell priming¹⁰