Role of Bcl-2 in tumour cell survival and implications for pharmacotherapy

Authors


Crispin R. Dass, Department of Biomedical and Health Sciences, Victoria University, St Albans 3021, Australia. E-mail: crispin.dass@vu.edu.au

Abstract

Objectives  Bcl-2 is a protein that inhibits apoptosis, leading to cell survival. The Bcl-2 family has six different anti-apoptotic proteins, three pro-apoptotic proteins that are similar in structure, and other integrating proteins that function as promotors or inhibitors in the progression of apoptosis. In this discussion paper, we provide an overview of apoptosis, the role of Bcl-2 in normal cellular and molecular processes, and the role of Bcl-2 in tumour cell survival. It focuses primarily on anti-apoptotic Bcl-2, its activation in cancer, the manner in which it regulates the intrinsic and extrinsic mechanisms of apoptosis, and its broad molecular interactions with other critical proteins in the cell. Certain cancer treatments are reviewed and related directions for the future are presented.

Key findings  Apoptosis is common to all organisms – for eukaryotes it is a normal process of development and regeneration. The rate at which apoptosis occurs is critical to the survival of the organism, as too much can lead to the onset of degenerative diseases such as dementia, and too little may lead to cancer. FKBP-38 is a binding protein that has been discovered to be upregulated in highly aggressive cancers and binds to Bcl-2 rather than the pro-apoptotics to induce a state of hyper-mitosis. A short binding protein (Nur-77) provides new insights into Bcl-2 ‘masking’. Nurr-77 binds to Bcl-2 and exposes the BH3 domain, transforming it from a cancer promoter to an unorthodox cancer inhibitor. This presents in itself an interesting and exciting opportunity – increasing the rate of apoptosis in neoplastic cells that are usually protected by Bcl-2 activity at the mitochondria.

Summary  Development of drugs in the form of BH3-only and BH123 mimetic drugs provide a interesting avenue for cancer therapy for the future. Drugs that can either promote, or mimic anti-IAP activity such as Smac/Diablo would certainly be productive, thereby inducing apoptosis. Medicinal usage which can effectively suppress FKBP38 in Bcl-2-dependent cancers would provide further arsenal to combat apoptotic irregularities, particularly a treatment that is more dominant than kinetin riboside. WAVE-1 inhibitors may effectively suppress the phosphorylation of Bcl-2, thereby potentially reducing hyper-mitosis and increasing apoptosis. Recent findings shed molecular light on PDT, namely ER stress, and potential for anti-cancer therapy via either apoptosis or autophagy. A drug that can effectively upregulate Nurr-77, thereby masking the anti-apoptotic properties of Bcl-2, would indeed be life-saving for cancer patients.

Introduction

The study of one particular form of programmed cell death, known as ‘apoptosis’, has progressed remarkably, among the other forms of cell death, including necrosis and autophagy.[1] The important role of apoptosis as a determinant of tissue homoeostasis has been the subject of many reviews.[2–6] Defects in the molecular processes of apoptosis can lead to pathological conditions such as tumorigenesis, autoimmune diseases, neurodegenerative disorders and developmental abnormalities.[7–9] In response to apoptotic signals, various proteins are activated in a pathway-specific manner, and the classical caspase activation chain reaction is set in motion.[10] Various types of apoptotic signal cascade have been revealed so far. The important role of ‘apoptosis’ in tumorigenesis has been reviewed.[11] The acquisition of a state of tumorigenesis involves a multistep process whereby disturbance in physiological and genetically mediated programs results in unceasing cellular proliferation and lesion growth.[12] Thus, it is essential that the acquisition of these characters protects cells from being channelled into apoptosis. In addition, metastatic potential and chemotherapy resistance require the abrogation of apoptosis.[11,13,14] A single oncogene can be critical to tumorigenesis or tumours become ‘addicted’ to the oncogene for tumour maintenance and progression.[12] The latter is an ‘oncogene addiction’ hypothesis. Naturally, these addicted genes pose as suitable targets for tumour control.[10]

In this discussion paper, we provide an overview of apoptosis, the role of Bcl-2 in normal cellular and molecular processes, and the role of Bcl-2 in tumour cell survival. It focuses primarily on anti-apoptotic Bcl-2, its activation in cancer, the manner in which it regulates the intrinsic and extrinsic mechanisms of apoptosis, and its broad molecular interactions with other critical proteins in the cell. Certain cancer treatments are reviewed and related directions for the future are presented.

Overview of apoptosis

Apoptosis is a genetically programmed cell death, executed by several steps including DNA fragmentation, a decrease in cellular size, loss of function of the mitochondria, plasma membrane blebbing, and the production of apoptotic bodies. Mammalian cells exhibit intrinsic and extrinsic pathways of apoptosis. In the intrinsic or mitochondrial pathway, the B-cell lymphoma-2 (Bcl-2) family of proteins has a crucial role. The Bcl-2 family comprises three subfamilies, an anti-apoptotic family, a pro-apoptotic multidomain family and apro-apoptotic BH3-only protein family. Among the proteins regulating apoptosis, Bcl-2, Bcl-xl (Bcl-2 related protein long isoform), Bcl-w, Mcl-1, A1/BF11 and Bcl-B (in humans) are well documented, and exhibit anti-apoptotic functions.[15] The proteins in the first subset of the Bcl-2 family possess at least a single homology domain, hence the nomenclature – BH, derived from α-helical Bcl-2 homology (BH) domain. There are BH1–4 domains.[16] Anti-apoptotic group proteins possess all BH domains except for A1 and Bcl-B. The second subset, pro-apoptotic multi domain or BH1–3 proteins, are represented by Bax (Bcl-2-associated x protein), Bak (Bcl-2 homologous antagonist/ killer) and BOK (Bcl-2-related ovarian death gene/MTD).

The third subset are the BH3-only proteins, and the reason for naming it so is because the homology domain region in these proteins, in comparison with other members of the same family, is only identical in the BH domain.[17] The proteins consist of the BH3-only proteins which share only the short BH3 domain with members of the Bcl-2 family. BH3-only proteins are strictly regulated through both transcription and post-transcription mechanisms.[17] They are essential for initiation of apoptosis in various physiological conditions, including developmentally programmed cell death and stress-induced apoptosis.[6] BH3-only proteins are discussed in the following sections.

The intrinsic mechanism of apoptosis and Bcl-2

BH3-only proteins are pro-apoptotic and function as initial sensors of apoptotic signals that emanate from various cellular processes.[16] They release the inhibition imposed on Bax and Bak by the pro-survival proteins. They include Bcl-2-antagonist of cell death (Bad), Bcl-2-interacting killer, BH3-interacting domain death agonist (Bid), harakiri, NADPH oxidase activator 1, p53-upregulated modulator of apoptosis (Puma) and Bcl-2-modifying factor (Bmf).[2] All BH3-only proteins interact with and regulate the core Bcl-2 family proteins to promote apoptosis. This interaction, inducing a loss of mitochondrial function, occurs chiefly because of changes in permeability of the channels of the mitochondrial membrane. The effector molecule is cytochrome-c, and is propelled by cellular damage to initiate mitochondrial outer membrane permeability changes (MOMP).[16] Shut-down of the electron transport chain occurs, the mitochondria degenerate, releasing cytochrome-c between intermembrane spaces, which in turn activates caspase-9, and subsequently caspase-3, -6 and -7, which causes the cell to degrade. The caspase-9 activation is triggered by apoptosome. Apoptosome is an Apaf1-cytochrome c complex[16] (refer to Figure 1). However, the intrinsic pathway can proceed in the absence of caspase-9 or apoptosome in certain cell types. Taken together, this implies that the mitochondria, along with Bcl-2, are the ‘decision-makers’ for cellular suicide. Further downstream, and to effect cell destruction, cleavage of ICAD (inhibitor of caspase-activated DNase) is required for its inactivation and is achieved by caspase-3, while ICAD naturally inhibits CAD (caspase-activated DNase). Movement of CAD is then permissible from the cytosol elements and into the nucleus, functionally altering DNA. Once in the nucleus, DNA is cleaved and the following characteristics of apoptosis occurs: a decrease in cell membrane surface area, loss of mitochondrial function, chromatin condensation, nuclear envelope disassembly, cytoskeleton collapse, blebbing of the plasma membrane, and production of apoptotic bodies.[18]

Figure 1.

One intrinsic mechanism of apoptosis. Several factors in cellular stress pathways lead to the inhibition of survival factors and Bcl-2. Bax leads to the release of cytochrome c from the mitochondria. The apoptosome forms via stimulation of Apaf-1, and triggers activation of pro-caspase-9 to caspase-9. Caspase-9 activates pro-caspase-3 to caspase-3. Caspase-3 executes full-blown apoptosis, and the cell breaks down into apoptotic bodies, which are ingested by macrophages.

The extrinsic mechanisms of apoptosis and Bcl-2

In the extrinsic pathway, ligand stimulation of the death receptors incites apoptosis. These are members of the tumour necrosis factor receptor (TNFR) family, such as Fas, which have an intracellular death domain. Here we describe the FasL-Fas pathway as an example of the extrinsic pathway. A selection of cells within the body express on the surface of the plasma membrane a Fas (also referred to as CD95 or Apo1) receptor that can attach to, and thus activate, the associated Fas ligand, in part due to protein crossover.[19] The propulsion of the Fas-dependent pathway leads to a further accumulation of cysteine proteins called caspases.[20] The extrinsic pathway is also called the death receptor pathway, due to the fact that ligation of death receptors from the tumour necrosis factor (TNF) family occurs.[21]

The extrinsic mechanism of apoptosis occurs when a Fas ligand latches onto a Fas receptor on the cell surface membrane, which leads to caspase-8 and FADD (Fas-associated death domain) recruitment in the plasma membrane. From this point onwards, the cell faces two options: (i) caspase-8 can activate the executioner caspases, which can directly degrade the cell into tiny sub-particles for apoptosis or (ii) Bid has a direct effect on tBid and, via inhibition of Bcl-2 (and Bcl-xL), stimulates the release of cytochrome c from the mitochondria. Once this occurs, Apaf-1 triggers caspase-3 to fully induce cell to apoptosis (refer to Figure 2). It is important to note, however, that the intrinsic and extrinsic pathway normally work independently, rather than in conjunction, except in hepatocytes.[21]

Figure 2.

The extrinsic mechanism of apoptosis. Cellular stress causes an extracellular signal, Fas ligand, to attach to its receptor – Fas receptor. This leads to the activation of FADD (Fas-associated death domain) and pro-caspase-8 at the level of the plasma membrane. Pro-caspase-8 is activated to caspase-8. Then, there are two alternative routes: caspase-8 may directly lead to the stimulation of caspase-3, -6, or -7, as caspase-8 is now cleaved, and the cell is ready to undergo apoptosis; alternatively, caspase-8 causes cytochrome c to be released from the mitochondria.

Apoptosis is not limited to the intrinsic and extrinsic pathways. Cellular stress induces the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Cellular stress inducers include hypoxia, oxidative injury, protein inclusion bodies, hypoglycaemia, high-fat diets, viral infections and cytotoxic drugs. The accumulation of unfolded proteins triggers an evolutionarily conserved series of signal transduction events, including apoptosis.[22] While Bcl-2 is a key player in intrinsic pathways, it plays an important role in extrinsic pathways and ER stress pathways as well. We would like to demonstrate the more precise mechanism of each pathway in the following section.

Tumorigenesis and apoptosis – from the viewpoint of Bcl-2

Deficiencies in apoptosis are no more important than in cancer. Lack of apoptosis impinges on both the effectiveness of treatment and the survival of the patient. It appears that the pro-apoptotic family members Bax and Bak are crucial for inducing permeabilisation of the outer mitochondrial membrane (OMM) and the subsequent release of apoptogenic molecules (such as cytochrome c and Smac/Diablo), which leads to caspase activation.[16] The anti-apoptotic family, including Bcl-2 or Bcl-xL, inhibit Bax and Bak OMM permeabilization triggered by BH3-only proteins. (refer to Figure 3). Smac/Diablo is described below, together with their close relationship with inhibitors of apoptosis proteins (IAPs). Current research involves synthesis of BH3-only mimetic drugs in the treatment of Bcl-2-dependent cancers. There appears to be an apoptotic regulatory switch that turns the pendulum of BH3-only protein upregulation to Bcl-2 upregulation, which has an effect on the rate of apoptosis.

Figure 3.

Role of Bcl-2 in inactivation of BH123. In the presence of upregulation of the anti-apoptotic protein Bcl-2, an apoptotic stimulus will become null and void. This is due to the fact that this mechanism of up-regulation propels Bcl-2 to deactivate BH123 proteins and the pro-apoptotic proteins (mainly Bax and Bad) remain in a partially activated state within the intermembrane space of the mitochondria.

The ‘rheostat’ model was proposed in 1990 in an attempt to explain the irregularities of the apoptotic switch. The core of the model states that between the anti-apoptotic and pro-apoptotic proteins, normally there is a balance, and the one that is greater in abundance in the mitochondria will govern the survival of the cell. If pro-apoptotic proteins are more abundant, then apoptosis will occur – pro-death, whereas if anti-apoptotic proteins are more abundant apoptosis will not occur – pro-survival. In addition, it was believed initially that when Bax interacts with Bcl-2, Bax was inhibited by a method called sequestration,[23] but currently this is not accepted within scientific circles.

Through the course of time, this model underwent evolution as it was revealed that Bax existed in the cytosol as a monomer, and that Bcl-2 bound to Bax did not result in inhibition.[24] In another model, BH3-only proteins operate as receptors on the plasma membrane, and bind other pro-apoptotic proteins and they are allowed to pass from the intermembrane (IM) space, through the mitochondria and into the cytosol. In this manner, they are prevented from accumulating in the IM space, and cytochrome c permeates through the mitochondria and into the cytosol.[25]

In yet another alternative version of the model, which we present here, BH3-only proteins inhibit Bcl-2 allowing multidomain proteins to form channels whereby molecules such as cytochrome c can be expelled from the mitochondria. When cellular stress overwhelms the cell whereby Bcl-2 is no longer the promoter, BH3-only becomes the forerunner and permeabilises the membrane in such a manner that the pro-apoptotic proteins and cytochrome c traverse the membrane and escape the mitochondria, allowing apoptosis to occur. Normally, the intrinsic mechanism predominates in these circumstances, evoked by a cytochrome c-dependent mechanism. In this model, apoptosis is regulated by ligated BH3 proteins, which recruit multiple Bcl-2 homologues rather than Bax or Bak ([26] refer to Figure 4). Despite the above model being poorly defined, either will result in MOMP changes and the pro-apoptotic members (cytochrome c, Smac/Diablo, and apoptotic inducing factors (AIFs)), pass through the membrane and elicit apoptosis.[27] The arsenal for oncogenesis is also dependent on hypostimulation of pro-apoptotic proteins, or hyperstimulation of anti-apoptotic proteins (hypo-apoptosis).

Figure 4.

Role of pro-apoptotic multidomain proteins. Cellular stress causes inactive multidomain proteins to become activated by blockade of Bcl-2. Pro-apoptotic multidomain proteins (Bax and Bad) are aggregated and result in release of cytochrome c to the cytosol, which heralds the onset of apoptosis.

Bcl-2 regulation and its involvement with tumorigenesis

Bcl-2 is an anti-apoptotic protein expressed on the outer membrane of the mitochondria. Its overall role is to inhibit multidomain and BH-3 only proteins, which prevent cytochrome c and Smac/Diablo release from the mitochondria, thus preventing apoptosis. The rate at which Bcl-2 is regulated depends on post-translational translocation and processing in the cell, for example phosphorylation, which activates Bcl-2. Kang et al.[28] discovered that another protein, WAVE1, aids the regulation of phosphorylation of Bcl-2 in leukaemia cells. In addition, Bcl-2 becomes localised to trigger off this event. The multidomain portion of Bcl-2 has an overall role of signalling to other Bcl-2 members to traverse the IM space and trigger off the caspase-dependent apoptotic cascade in response to certain types of cellular stress such as reperfusion (refer also to Figure 4).

Notably, the number of BH3-only proteins present in humans and metazoans is more than a dozen perhaps explaining the reason why, together with caspases, higher species tend to live a longer and more adapted lifestyle by being able to ‘tweak’ the mechanisms of apoptosis. Interestingly, Bid becomes the effector protein in the extrinsic mechanism of apoptosis, or the death receptor pathway, since it receives apoptotic stimuli and transfers them via its cleaved product (truncated Bid) from the mitochondria.[29]

In the cell, if there is a survival factor present within the extracellular matrix, it can bind, via an acceptor site, to its receptor on the cell. A gene-regulatory protein then becomes activated within the cytosol and then acts on the nucleus, stimulating the production of Bcl-2, thus blocking apoptosis. Apoptosis can also be blocked by inactivation of the BH3-only Bcl-2 proteins, where the activation of a survival factor via an activated receptor leads to Akt kinase being activated. Normally, Bad is active when it is not phosphorylated and attached to Bcl-2, but the phosphorylation of Bad, together with Bcl-2, leads to the prevention of apoptosis.

Growth factors also regulate apoptotic pathways (e.g. PI3K (phosphatidylinositol-3 kinase) and Akt (v-Akt murine thymoma viral oncogene homologue)) in a nuclear derived pathway. The mechanism behind the pathway is that growth factors bind to their specific receptors, which leads to the activation of a PI3K-dependent pathway. PI3K activates Akt, which drives Bad (Bcl-2 antagonist of cell death) expression. Therefore, Bad has the important role of interacting with Akt, and this is one mechanism whereby growth factors acting from outside the cell dictate either the promotion or inhibition of apoptosis, specifically at the mitochondrial membrane.[30]

Bcl-2 and Nur77

Recent research into apoptosis has revealed that anti-apoptotic Bcl-2 has ‘two faces’. Lin et al.[31] report that Bcl-2 interacts with the orphan nuclear receptor Nur77, which is needed by a number of anti-cancer drugs to induce cancer cell apoptosis. The interaction is mediated by the N-terminal loop region of Bcl-2 and is required for Nur77 mitochondrial localization and apoptosis. Nur77 binding induces a Bcl-2 conformational change that exposes its BH3 domain. Intriguingly, it changes Bcl-2 from a protector to a killer. This data demonstrates novel strategies for regulating apoptosis in cancer and other diseases.[31] Therefore, development of anti-cancer drugs which upregulate Nur77 would indeed be life-saving in the future for those cancers where Bcl-2 is upregulated. Nur77 is often translocated from the nucleus to the mitochondria where it responds to many different death signals and thus the biochemical structure of Bcl-2 is changed.[32] A Bcl-2 converting peptide derivatised from Nur77, nine amino acids long (NuBCP-9, or Nur77 Bcl-2 converting peptide with 9 amino acids), has been demonstrated to stimulate apoptosis in vitro and in animals. NuBCPs are activated by Bax, a pro-apoptotic molecule of the BH3 family. Enantiomers bind to the BH3 loop, which has implications for many cancers and cell signalling pathways, thereby prising apart the Bcl-2 BH4 domain and activating the BH3 domain, which stimulates apoptosis by blockade of Bcl-xL.

The Bcl-2 family also control the initiation of autophagy, an evolutionarily conserved process for maintaining cell survival by self-cannibalism of cellular components, including organelles, in cells undergoing starvation. Beclin-1 is an essential protein for initiation of autophagy. It binds to anti-apoptotic Bcl-2 family members[33] via a BH3-like domain.[34,35] The association of Beclin-1 with anti-apoptotic Bcl-2 family proteins prevents activation of PI3 kinase, inhibits apoptosis and triggers autophagy.[34,35] Accordingly, a BH3-only protein and a BH3 mimetic compound such as ABT-737 can dissociate Beclin-1 from anti-apoptotic Bcl-2 family members and allow autophagy. Bcl-2 on the ER, not on the mitochondria, can inhibit autophagy induction.[33,36]

Kessel[37] also investigated apoptosis enhancement via photodynamic therapy (PDT). The objective of the study was to determine the effect of PDT on the ER at various wavelengths and intensity. The main finding, apart from the fact that stress to the ER causes apoptosis, was that PDT causes degeneration of the ER, but, in fact, also has an effect on anti-apoptotic Bcl-2. The doses used only caused a small deterioration, though it was clearly seen that PDT increased the pro-apoptotic effects of the ER with Bcl-2 being suppressed as part of the phenomenon. This was due to phototoxic effects that damaged the ER, and provides some vital clues as to why PDT causes cell death in various cancer cells.[37]

Edlich et al.[38] demonstrated that Bcl-xL inhibits and maintains Bax in the cytosol by constant retrotranslocation of mitochondrial Bax. Furthermore, Bax retrotranslocation depends on BH3 interactions with prosurvival Bcl-2 proteins. Overexpression of Bcl-2 and Mcl-1 accelerated Bax retrotranslocation similarly to Bcl-xL. In contrast, the BH3-only protein Bim reduced the rate of Bax retrotranslocation. Furthermore, the Bcl-2/Bcl-xL inhibitor ABT-737 reduced the rate of Bax retrotranslocation by more than 75%, suggesting that endogenous Bcl-2 family members mediate Bax retrotranslocation. These results indicate the involvement of direct interactions between prosurvival Bcl-2 proteins and Bax for retrotranslocation.

Leukaemia is a malignant disease of the bone marrow and blood, and is the most common form of cancer in children.[39] Acute lymphocytic leukaemia is one such example where Bcl-2 is upregulated, leading to the hyperproliferation of leukocytes. Indeed, the upregulation of Bcl-2 has been associated with many cancers, including breast cancer, B-cell derived lymphoma, colon cancer and prostate cancer. A protein that has been found to be upregulated in many tumours is FKBP38 (FK506-binding protein-38), which is highly present in aggressive cancers. Initially, Nielsen et al. reported FKBP38 as a novel isoform of FKBPs and it has been implicated in the regulation of apoptosis.[40] The protein is usually located in mitochondrial outer membranes and the membranes of the ER and has been found to regulate apoptosis at these sites. When FKBP38 is allowed to accumulate, it can lead to autoimmunity and neurodegeneration.[41] The presence of FKBP38 in cells stabilises Bcl-2 through a loop binding region resulting in prevention of Bcl-2 degradation by caspases-3 and -9, and blockade of de-novo protein via post-translational mechanisms. FKBP38 protection of Bcl-2 is controlled by calmodulin-Ca2+.[42] Thus, FKBP38 promotes cell survival, which may lead to cancer. One basis for cancer treatment is to block the Bcl-2 and the Bcl-xl pathways by FKBP38 inhibition.[41] In fact, according to the National Cancer Institute (NCI), which has investigated up to sixty different cell lines, Bcl-2 hyperstimulation leads to cancer therapeutic resistance in all cell types, and against nearly all therapeutic mediators.[43] When kinetin riboside, an anti-cancer drug, is administered, it is rendered inefficient in cancers where FKBP38 is upregulated and Bcl-2 has consequently accumulated.[41] This occurs despite the fact that kinetin riboside downregulates Bcl-2, but in the presence of FKBP38, kinetin riboside is suppressed and consequently cells survive. The reduction of FKBP38 by small interfering RNA (siRNA) induces a loss of Bcl-2 protein in a transcription-independent manner. However, when caspase inhibitors are activated once again, the process is significantly reversed. As mentioned above, FKBP-38 binds to Bcl-2 via a flexible loop domain, which contains the caspase-3 cleavage site.[41] The inhibition of the caspase cleavage site by FKBP38 is a characteristic of cancer progression.

The upregulation of Bcl-2 has been implicated in breast cancer, particularly in cancers where the tumour cells rely on oestrogen for maintenance and progression. Interestingly, Lewis-Wambi et al.[44] discovered that oestrogen has the ability to both induce and suppress tumour cell formation in the development of breast cancer through oestrogen receptor-mediated signalling.

Summary

In summary, a brief overview of the mechanisms of cancer, of apoptosis, and Bcl-2 molecular biology has been reviewed in this paper. Bcl-2 belongs to a peculiar, though powerful, family of proteins consisting of both pro-apoptotic (Bim, Bad, Noxa, PUMA) and anti-apoptotic proteins (Bcl-2 and Bcl-xL). The role of Bcl-2 is to prevent apoptosis from occurring by blocking cytochrome-c and Smac/Diablo release from the mitochondria, as well as being an antagonist to BH3-only proteins, thus inactivating caspases. In mammals, apoptosis is executed via tightly regulated intrinsic and extrinsic pathways. Bcl-2 is responsible for inactivating both intrinsic and extrinsic mechanisms of apoptosis. A fine homoeostatic balance exists between cell death and cell growth in the healthy individual, and cancer disrupts this homoeostasis. An examination of the biochemical structure of Bcl-2 has shown that the protein WAVE-1 is involved in the regulation and phosphorylation of Bcl-2 during leukaemia. Further investigation is required in order to facilitate an anti-cancer mechanism by the inhibition of WAVE-1. Promising findings exists regarding the activation of a short Nurr-77 derived protein, which has the ability to expose the BH3 domain and evoke pro-apoptotic cellular mechanisms of Bcl-2. The above-mentioned therapies may be implemented in the future for cancer patients, and the future looks promising and is heading towards tailored molecular therapy. Anti-Bcl-2 agents form one class of promising drugs for the future against cancer.

Future directions

Development of drugs in the form of BH3-only and BH123 mimetic drugs provide a interesting avenue for cancer therapy for the future. Drugs that can either promote, or mimic anti-IAP activity such as Smac/Diablo would certainly be productive, thereby inducing apoptosis. Medicinal usage which can effectively suppress FKBP38 in Bcl-2-dependent cancers would provide further arsenal to combat apoptotic irregularities, particularly a treatment that is more dominant than kinetin riboside. WAVE-1 inhibitors may effectively suppress the phosphorylation of Bcl-2, thereby potentially reducing hyper-mitosis and increasing apoptosis. Recent findings shed molecular light on PDT, namely ER stress, and potential for anti-cancer therapy via either apoptosis or autophagy. A drug that can effectively upregulate Nurr-77, thereby masking the anti-apoptotic properties of Bcl-2, would indeed be life-saving for cancer patients.

Declarations

Conflict of interests

The Author(s) declare(s) that they have no conflicts of interests to disclose.

Funding

This review received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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