BAX, a new target for cancer therapy?

By Themis Halka

Cancer remains in today’s society a great challenge for scientists, doctors and patients. Even though numerous cancers can be treated with relatively good outcomes via surgery (radiotherapy and chemotherapy), these techniques are not miraculous and come with important side effects. Intensive research targets the development of new ways to treat cancer, using non-invasive methods targeting specific pathways of the cells function. Recent discoveries highlighted the potential of targeting BAX protein to promote tumour cells apoptosis, in order to control the tumour growth and resorb it.

BAX is a protein present in most cells of our body, including most cancer cells. It is part of the Bcl2 protein family, which plays a crucial role in cell death regulation, comprising both anti-apoptotic and pro-apoptotic proteins. BAX is involved in the activation of mechanisms leading to apoptosis (GeneDatabase, 2021). In fact, if BAX is under normal circumstances located in the cytosol, it is after activation translocated in the mitochondrial outer membrane, where it causes its permeabilization (GeneDatabase, 2021). The mitochondrial outer membrane permeabilization affects, in particular, cytochrome c, a molecule usually bound to the fourth complex of the electron transport chain that is involved in energy production. Due to the permeabilization of the membrane, cytochrome c migrates from the mitochondrial intermembrane space to the cytosol, where it interacts with apoptotic protease activating factors (Cai et al., 1998). It leads to the activation of caspase-3 cascade, which in turn activates other caspases and mechanisms leading to cell death (Cai et al., 1998).

In order to prevent undesired activation of BAX, it is allosterically regulated, in normal circumstances, by the binding of anti-apoptotic proteins from the Bcl2 family, in particular Bcl2, with whom BAX forms a heterodimer. Under this configuration, BAX contains hydrophobic parts, and is hence unable to translocate to the mitochondrial membrane (Liu et al., 2021). BAX interacts with Bcl2 via its BH3 domain. However, other proteins can also interact with BAX’s BH3 domain, in particular BH3-only proteins that will activate BAX, disrupting its interaction with Bcl2. This configurational change leads BAX to acquire the ability to translocate into the mitochondrial outer membrane, where it can play its pro-apoptotic role (Liu et al., 2021).

Because of this dimerization of BAX with Bcl2 in the cytosol, key to the regulation of BAX, the measure of the BAX/Bcl2 ratio is an indicator of the state of the cell. An over expression of BAX, resulting in an increase in BAX/Bcl2 ratio, would lead to cell apoptosis, with enough BAX proteins being able to migrate to the mitochondrial outer membrane. In contrast, the overexpression of Bcl2 would cause the cell to lose its apoptotic activity, being unable, even when triggered by signalling factors, to activate its apoptotic pathway (Vaskivuo et al., 2002).

This decrease in the BAX/Bcl2 ratio is observed in a great number of cancers (Liu et al., 2021). The overexpression of Bcl2 leads to an uncontrolled tumour growth, as BAX can’t perform its apoptotic function, generally triggered when the tumour development starts. This has consequences on the resistance to treatments; BAX inhibition is a major factor explaining the resistance to chemotherapy (Adams et al., 2007). Studies have also shown BAX-deficient colon carcinoma cells to be insensitive to death-receptor ligands, which should trigger an apoptotic response, while their BAX-expressive clones were receptive to the ligand binding (LeBlanc et al., 2002). Moreover, it has been estimated that mutations of BAX leading to its loss of function were present in approximately 21% of human haematopoietic malignancies (Meijerink et al., 1998). Hence, it seems that BAX inhibition or loss of function is an important factor leading to rapid and uncontrolled tumour growth, as it prevents the cell from performing apoptosis. Triggering BAX activation could be a possible option to fight cancer.

A number of cancer drugs in the clinical market already participate indirectly to the activation of BAX. The use of histone deacetylase inhibitors for instance favours the expression of BAX, by preventing the deacetylation of p53 and BAX gene DNA segments, which participates in making them more accessible for transcription, hence increasing BAX expression (p53, a tumour-suppressing gene, regulates the expression of BAX) (Uo et al., 2021). Currently, research is being concentrated on developing small-molecule drugs specifically targeting the activation of BAX, in order to find more specific approaches to induce cell apoptosis (Liu et al., 2021).

During the last few years, several drugs were developed, in particular BH3-mimetic drugs. These drugs target the anti-apoptotic members of the Bcl2 family, aiming to prevent their interactions with BAX and other pro-apoptotic proteins, by binding their BH3 site (Campbell et al., 2021). Venetoclax has shown great efficiency, by specifically targeting Bcl2’s BH3 binding site via the ABT-199 molecule (Campbell et al., 2021). In chronic lymphocytic leukaemia, the efficacy of the agent when applied alone induced a partial response in 79% of the patients and a complete response in 20% of the patients (Roberts et al., 2016). The combination of Venetoclax with other drugs was even more impressive. Further research is yet to be made, for instance to investigate a possible direct activation of BAX by allosteric binding. An option is to take advantage of the unique sites possessed by BAX but no other Bcl2 family members (Liu et al., 2021). These sites specific to BAX can be targeted to favour its activation, which will ensure that no other potentially anti-apoptotic family members will be activated, causing dramatic outcomes. BAX could therefore be specifically activated in order to increase the cancer cells’ apoptotic response.

The possibilities of Bcl2 family members regulation are very promising indeed, not only in cancer but in other diseases showing uncontrolled cell resistance or death, in neurodegenerative diseases for example. The activation of BAX isn’t a miracle solution that could cure all cancers and replace the current invasive and non-invasive techniques. However, in certain cases, where BAX is functional but inhibited by an unbalanced BAX/Bcl2 ratio, it could lead to improved outcomes, and save lives.

References:
GeneDatabase, 2021. BAX Gene – GeneCards | BAX Protein | BAX Antibody. [online] Genecards.org. Available at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=BAX [Accessed 27 January 2021].

Cai, J., Yang, J. and Jones, D., 1998. Mitochondrial control of apoptosis: the role of cytochrome c. Biochimica et Biophysica Acta (BBA) – Bioenergetics, 1366(1-2), pp.139-149.

Liu, Z., Ding, Y., Ye, N., Wild, C., Chen, H. and Zhou, J., 2021. Direct Activation of Bax Protein for Cancer Therapy. Available at : 10.1002/med.21379

Vaskivuo TE., Stenbäck F., Tapanainen JS., 2002. Apoptosis and apoptosis-related factors Bcl-2, Bax, tumor necrosis factor-alpha, and NF-kappaB in human endometrial hyperplasia and carcinoma. Cancer. 2002 Oct 1; 95(7):1463-71.

Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324–1337. Available at : 10.1038/sj.onc.1210220

LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P, Fong S, Schwall R, Sinicropi D, Ashkenazi A. Tumor-cell resistance to death receptor–induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med. 2002;8(3):274–281.

Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Sloetjes AW, de Witte T, Waksman G, Korsmeyer SJ. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood. 1998;91(8):2991–2997.

Uo, T., Veenstra, T. and Morrison, R., 2021. Histone Deacetylase Inhibitors Prevent p53-Dependent and p53-Independent Bax-Mediated Neuronal Apoptosis through Two Distinct Mechanisms. Available at : 10.1523/JNEUROSCI.6186-08.2009

Campbell, K. and Tait, S., 2021. Targeting BCL-2 regulated apoptosis in cancer. Available at : 10.1098/rsob.180002

Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28; 374(4):311-22.

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