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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 147-151

Bacterial protein azurin and tumour suppressor p53 in cancer regression


Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka

Date of Submission06-Jul-2020
Date of Acceptance05-Oct-2020
Date of Web Publication09-Feb-2021

Correspondence Address:
Chamindri Witharana
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Colombo, Colombo
Sri Lanka
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AIHB.AIHB_69_20

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  Abstract 


Cancer as a cause of frequent illness and death possess a significant threat for the global public health. At a time where the existing conventional therapies such as chemotherapy, radiotherapy, surgery and monoclonal antibodies demand modifications due to their limitations such as toxicity and acquisition of resistance, microbial peptides have revived attention. Azurin is a bacterial cupredoxin secreted by Pseudomonas aeruginosa with the ability of preferential entry and cytotoxicity towards a wide variety of cancer cells in vivo and in vitro. It provides the promise of overcoming resistance due to being a multitargeted anticancer agent showing extracellular mode of action by interaction with several cell surface receptors and intracellular action by interacting with tumour suppressor p53 and interfering in its pathway. Tumour suppressor p53 is frequently mutated in Human cancers and thus the ability of azurin and its peptides to stabilise p53 to revive its functions opens up a revenue of opportunities for exploration in cancer therapeutics. This review aims to discuss about azurin and its peptide p28, the molecule which completed two Phase 1 clinical trials and tumour suppressor p53 for new prospects for the future.

Keywords: Azurin, tumour suppressor p53, p28, cancer


How to cite this article:
Lakshani Dharmawickreme RB, Witharana C. Bacterial protein azurin and tumour suppressor p53 in cancer regression. Adv Hum Biol 2021;11:147-51

How to cite this URL:
Lakshani Dharmawickreme RB, Witharana C. Bacterial protein azurin and tumour suppressor p53 in cancer regression. Adv Hum Biol [serial online] 2021 [cited 2021 Sep 25];11:147-51. Available from: https://www.aihbonline.com/text.asp?2021/11/2/147/309598




  Introduction Top


Characterised by uncontrolled growth of abnormal cells in the body, cancer is a global threat, with incidence still rising at an alarming rate. Although conventional therapy has increased survival rates against cancer, non-specific toxicity towards normal body cells, acquisition of resistance and side effects have limited their effectiveness and increased the requirement of alternative strategies against cancer.[1],[2] Utilisation of live or attenuated pathogenic bacteria or their products in the treatment of cancer was long been known,[3] but the ambiguity with dose, immunogenicity and toxicity had restricted their usage.[1],[2] However, the recent discoveries of novel proteins and peptides of bacterial origin and the availability of genetic engineering techniques have reviewed the interest and rekindled the idea of using pathogenic bacterial products in the treatment of cancer.[2] Azurin and its peptide p28 have demonstrated the ability of preferential entry and antitumour activity by post-translational stabilisation of p53, providing new opportunities for the future.[4],[5],[6],[7]


  Background Top


Azurin is a Type 1 cupredoxin protein secreted by the pathogenic bacterium Pseudomonas aeruginosa. According to the X-ray structure at 1.93 A°, azurin consists of an alpha-helix, 8 beta-strands arranged in a Greek key motif and copper ion coordinated by three strong equatorial ligands and two weaker axial ligands.[8] Revealing a novel function, the protein contributing to the bacterial denitrification process was identified to lead J777 macrophages to apoptosis.[9] Later with the finding of the ability of preferential entry and cytotoxicity towards cancer cells such as human melanoma UISO Mel 2 and breast cancer cells MCF 7 Azurin came under the spotlight attracting the attention of Scientists as a potential anticancer agent.[4],[5] Azurin came under the spotlight, attracting the attention of scientists as a potential anticancer agent. Azurin expression was also found to inhibit B16 melanoma and 4T1 breast tumour growth in mouse models.[10] Azurin with its scaffolding properties was identified to interact with multiple extracellular and intracellular targets and interfere with different pathways such as EphB2 receptor tyrosine kinase signalling.[11] Vascular endothelial growth factor receptor (VEGFR)–2 allows inhibition of angiogenesis[12] and inhibition of cell invasion by decreasing P-cadherin expression in breast cancer cells.[13] Although being a multitarget anticancer agent, azurin is found to set off the death sequence mainly by stabilising the well-known tumour suppressor p53 by complex formation and inducing apoptosis.


  p53 Top


Tumour suppressor p53 is a transcription factor involved in a myriad of signalling pathways. Normally present in low levels due to the effect of negative regulators such as MDM2, p53 is stabilised by post-translational modifications with rise of intracellular levels activating downstream target genes in order to bring about cell cycle arrest, DNA repair and apoptosis upon sensing DNA damage or stress conditions.[14] In other words known as the guardian of the genome, p53 conserves the genomic integrity, preventing carcinogenesis.[15],[16] Therefore, the deregulation and loss of function of p53 is a major cause of malignancy, and studies have revealed that 50% of cancers are associated with p53 mutation, making it a promising anticancer target.[15]


  Structure and Properties of p53 Top


p53 composed of 393 amino acids exists as a tetrameric protein with four identical subunits. Each monomer is known to comprise three main domains with respective functions: N–terminal transactivation domain (NTD), a core DNA binding domain (DBD) and a C terminal domain (CTD). N terminal domain which is in charge of activation of transcription factors includes transactivation domain and a proline-rich fragment important for the apoptotic activity. The core domain is identified as the region responsible for DNA binding and is considered to be a mutation hotspot. Moreover, the mutations in this region are often associated with loss of tumour suppressor function. Tetramerisation domain responsible for the tetramerisation of the protein as well as nuclear localization signal (NLS) and a nuclear export signal (NES) is found towards the C-terminus in the CTD.[17],[18]

Belonging to a family of intrinsically disordered proteins, p53 exhibits different conformations under different physiological conditions.[19] The plasticity and scaffolding properties of p53 allow it to interact with various other biological molecules in order to perform its tumour suppressor function.[20]


  p53-Mediated Mechanism of Action of Azurin Top


As structural stability and appropriate intracellular levels of the protein are important for its anticancer function, strategies that could stabilise p53 and counteract the effect of its downregulators should provide the promise of restoration of p53 function.[21] Standing through multiple mechanistic studies, azurin has proven its anticancer activity by similarly interfering in p53 pathway stabilising and subsequently increasing protein levels and restoring its tumour suppressor function.

One of the initial evidences on this mechanism of action of azurin was revealed in the study on J774 macrophages where apoptosis was induced with an increase of reactive oxygen species (ROS).[9] However, several redox negative azurin mutants also generated ROS-inducing macrophage apoptosis, implying that the cytotoxicity of azurin is not related to its redox activity,[22] rather the evidence from glycerol gradient centrifugation analysis confirmed that azurin-induced apoptosis was through the complex formation and stabilisation of p53, increasing its intracellular levels.[9]

Similar evidence for the p53-mediated anticancer activity of azurin came from the experiments on human cancer (melanoma UISO-Mel-2) cells where apoptosis was identified to initiate through the induction of caspase cascade after azurin-dependent stabilisation of p53 and transcriptional activation of pro-apoptotic genes.[5] On the other hand, reduced cytotoxicity on p53-null mutant cancer cells further supported the fact that the anticancer activity of azurin is dependent on the p53 status in cancer cells.[4],[5]

Investigations on the azurin levels in different subcellular compartments in p53-null mutant melanoma cells compared to the functional melanoma cells further inferred that intracellular trafficking of azurin to the nucleus is p53 dependent.[4]


  Further Insight into Azurin and p53 Interactions Top


Looking further into azurin and p53 interactions, few studies have indicated that azurin forms a complex with full-length p53,[9],[23] and they bind with a stoichiometry of 4:1 as confirmed by isothermal calorimetry.[18] The same was validated by surface plasmon resonance and atomic force microscopy experiments,[21],[24] while several others revealed on the possible interactions of azurin with NTD, DBD and perhaps CTD of p53 separately.[25],[26],[27]

However, as illustrated by site-directed mutagenesis, hydrophobic patch of azurin usually involved in redox interactions with other partners and two methionine residues on positions 44 and 64 in this region is considered to be crucial for its p53 interactions.[22],[28]

DBD of p53 is one of the most investigated on possible azurin and p53 interactions.[19],[26],[28] Protein docking and free energy stimulations have suggested that azurin binds to the most unstable L1 and S7–S8 loops of the p53 DBD via its hydrophobic patch stabilising p53 DBD through protein–protein interactions.[26] In agreement with the computational simulations, results from Raman spectroscopy confirmed that azurin induces conformational change of DBD structure upon binding, lowering its conformational heterogeneity.[19]

NTD of azurin exists as an unstructured domain in solution.[16] Containing binding site for MDM2, the main deregulator of p53, is a probable target for protein association. Several investigations from computer simulations to biophysical studies have been carried out to probe the probable azurin–NTD interactions.[8],[18] As recorded by a fluorescence study, decrease of tryptophan emission was observed with an increase in secondary structure, which can be attributed to azurin Cu 2+ effect on binding to NTD.[18] A computational study carried out on the same has suggested the probable binding of azurin to helices HI and HIII which are hypothesised to overlap with the MDM2-binding region.[8]

The region corresponding to 15–29 residues of transactivation domain has attracted the attention of scientists as a MDM2-binding site.[16] Contradicting with previous indications, fluorescence and phosphorescence spectroscopic investigations suggest that azurin binding site of NTD is different from that of MDM2.[25] Furthermore, surface plasmon resonance evidences pointing towards a possible ternary interaction of the three proteins azurin, MDM2 and p53 indicated that azurin modulates the MDM2–p53 binding kinetics by reducing association rate constant not through competing with MDM2 but via an allosteric mechanism.[21]

Compared to p53 DBD and NTD, literature is sparse on possible azurin and CTD interactions. Moreover, Glutathione S transferase (GST pull down assay) pull-down assay only indicated weak interactions.[29] However, the insight into CTD is of importance because its mutations have been associated with p53 ubiquitination and degradation.[27] Another interesting feature on this domain is that it has the ability to interact with nucleic acids, changing the structure of p53, and thus modulate interactions with other proteins. In a similar study, nucleic acid-mediated interaction of azurin with CTD was detected, supporting the possibility that nucleic acid might allosterically regulate the CTD confirmation, aiding p53–azurin interaction.[27]

Therefore, considering the literature so far what is evident is that there are still many open issues and contradictions regarding azurin–p53 interactions that have to be addressed in order to extract the maximum utility of azurin as an anticancer therapeutic.

At the same time, immunogenicity is a significant hindrance that compromises the pharmaceutical efficacy of a protein which could be the same in case of azurin. In realisation, scientists have been able to unravel a truncated version of azurin, which affirms the same therapeutic efficacy with target specificity, preferential entry and cytotoxicity, but with potentially less side effects. Therefore, the rest of this communication will be dedicated to the peptide fragment p28 for its p53-mediated mechanism of action as a potential anticancer agent.


  p28 Top


Possessing a molecular mass of 2.9 kDa, the peptide p28 corresponds to amino acids 50–77 of the bacterial cupredoxin azurin.[30] Consisting of an extended alpha helix with a β-strand, a turn and an irregular structure, p28 is stable and well folded when in association with the protein.[7] Being an amphipathic, anionic cell-penetrating peptide, it has exhibited function similar to azurin, resulting in tumour regression.[31] As a small molecule, it comes with an added advantage of no significant toxicity or adverse effects.[32],[33]


  Anticancer Action of p28 Top


Similar to azurin, p28 not only interacts with p53 but also interferes with other pathways.[7] For instance, p53-independent inhibition of angiogenesis and tumour growth was recorded in a study of p28 on human umbilical vein endothelial cells where p28 by interaction with VEGFR-2 caused inhibition of FAK and Akt phosphorylation.[12]

However, much evidence point towards the anti-proliferative action arising from stabilisation of p53.

According to a study on human breast cancer cell lines MCF-7, ZR-75-1 and T47D, p28 showed preferential entry into cancer cells through a caveolin-mediated pathway.[34]

The anti-proliferative activity of p28 was appeared to result from complex formation via hydrophobic interaction with DBD and post-translational stabilisation of p53, elevating its intracellular levels. The activation of p53 by p28 and posttranslational increase of expression of p53 and p21 with reduction of cyclin dependent kinase 2 and cyclin A, explains the induction of a G (2) M phase cell cycle arrest and apoptosis. [31],[34] with reduction of cyclin-dependent kinase 2 and cyclin A, explaining the induction of a G(2)-M-phase cell cycle arrest and apoptosis.[31],[34]

p28 reduced the level of FoxM1, which is also important in G2–M transition in p53wt MCF-7, Mel-29 and p53mut Mel-23 cells, and inhibited cell proliferation, but did not reduce the high basal levels of FoxM1 in triple-negative p53mut MDA-MB-231 cells.[35]

Furthermore, in silico computational simulations and mechanistic investigations on p28–p53 interactions revealing the potential binding sites of p28 as the L1 loop (aa 112–124); a region within the S7–S8 loop (aa 214–236) and T140, P142, Q144, W146, R282 and L289 of the p53DBD, indicated that p28 does not inhibit binding of MDM2, but blocks binding of constitutive morphogenic protein 1 (COP1) to wild type or mutant p53.[31],[35],[36]

COP1 which is significantly overexpressed in breast and ovarian adenocarcinoma is an E3 ubiquitin ligase that binds to a motif within DBD and decreases steady-state p53 levels.[36] Thus, the ability of p28 to block the COP1 binding to wild-type and mutant p53 increasing the DNA-binding activity without significantly altering its conformation adds to its importance in exploration as an anticancer therapeutic.[35],[36]


  Azurin and p28-Based Therapeutic Strategies Top


Endowed with target specificity, selective entry and ability to induce cell cycle arrest and apoptosis, azurin and its derived peptide p28 offer new perspectives to anticancer therapeutics.

Standing through two Phase 1 clinical trials, one in adults with metastatic solid tumours[32] and the other in children with brain tumours, p28 has affirmed its anticancer activity as a safe and well-tolerated agent.[33]

In addition to being effective alone,[10] azurin acts as a drug sensitiser when employed in combination with other anticancer drugs. Combined application with azurin increased the sensitivity of MCF-7 breast cancer cells, HeLa cervical cancer cells and HT-29 colon cancer cells to paclitaxel and doxorubicin.[37] Oral squamous carcinoma cells (YD-9) displayed increased sensitivity to 5-fluorouracil and etoposide.[38]

Cell-penetrating peptides (CPP) possess the ability to cross biological membranes, thus delivering bioactive cargo into cells. p28 being a CPP with preferential entry into cancer cells is ideal to be used in cancer-targeted drug delivery systems. Studies reveal that CPP can be conjugated to anticancer drugs through covalent or non-covalent strategies.[39] In an attempt to develop a HPV therapeutic vaccine, p28 has shown successful results with effective delivery of HPV16 E7 protein to cancer cells.[39] Chimeric protein of apoptin and p28 produced synergistic effects on breast cancer cell lines.[40] Granzyme B–azurin fusion produced selective effectiveness inducing apoptosis in MDA-MB-231, MCF7 and SK-BR-3 breast cancer cell lines with insignificant cytotoxicity to MCF 10A normal breast cells.[41] Whereas the chimeric protein produced by p28–NRC fusion showed additive effects, enhancing the cytotoxicity towards breast cancer cells than when applied alone.[42]


  Summary Top


Cancer as a global threat is a complex disease that demands new therapeutic interventions. Bacterial cupredoxin azurin and its peptide p28 are multitargeted anticancer agents which exert their action by interfering with multiple signalling pathways. Tumour suppressor p53 is a key regulator of cell cycle which plays a vital role in the prevention of carcinogenesis. Being susceptible to frequent mutation, it is recognised as an appealing target for cancer therapy. Past studies revealing details of p53-mediated mechanism of action have indicated that upon preferential penetration into cancer cells, azurin complexes with p53 DBD or NTD, counteracting the effects of its downregulators, stabilising and raising its intracellular levels. This in turn results in the activation of downstream targets, leading to cell cycle arrest, apoptosis and thus tumour regression. Although this knowledge has greatly improved our understanding on azurin and p53 interactions, there are still many open issues to be addressed such as ambiguity over the exact binding details. Therefore, further systemic investigations on the interactions and complex structures of azurin/p28 and p53 may lead to engineering more effective cytotoxic peptides from the azurin sequence. In addition, further insight into new functions of azurin and discovery of putative bacteriocins with functional similarity and evaluation of combinatorial therapeutic strategies might provide better perspectives to targeted cancer therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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