Investigating the use of bacterial peptides as anticancer drugs with emphasis on p28 peptide of Pseudomonas aeruginosa

Investigating the use of bacterial peptides as anticancer drugs with emphasis on p28 peptide of Pseudomonas aeruginosa
Zahra Naziri,¹ Zahra Rezaei,^2,* Zahra Gholizade Farshi,³
1. Department of Pathbiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
2. Department of Pathbiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
3. Department of Pathbiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
Introduction: The second leading cause of death in the world in 2018 was cancer. Despite the advances in diagnosis and treatment, cancer is one of the most important causes of death. The main problem in cancer treatment is the adverse effects of chemotherapy and radiation and lack of response to drug treatment in some malignancies. Therefore, it is crucial to conduct research to find new anticancer agents. Azurin and exotoxin A from Pseudomonas aeruginosa, Pep27anal2 from Streptococcus pneumoniae, diphtheria toxin from Corynebacterium diphtheriae, and Entap from Enterococcus sp. all have anticancer effects. Coley toxins, which refer to Streptococcus pyogenes, Serratia marcescens and their metabolites, were successfully used by William Coley in 1909 to treat cancer and unresectable tumors. The increase of TNF-α and the activation of lymphocytes and macrophages is the main reason for the anti-cancer activity and therapeutic use of these toxins. Proliferation of pathogenic microorganisms in hypoxic cancerous lesions stimulates the patient's immune system and inhibits the cancer progression. After binding to p53, p28 peptide from the azurin protein of Pseudomonas aeruginosa exhibits anticancer properties. Binding of p28 protein to DNA binding domain (DBD) and formation of p28-DBD complex causes tumor regression. So, in this short article, the mechanism of anti-cancer activity of p28 peptide has been reviewed.
Methods: The p28 peptide selectively enters human cancer cells through endocytosis via the caveolin receptor. Selective penetration occurs at neutral pH and is protected against intracellular protease or endonuclease. Since, Azurin-p28 is absorbed using energy and without the involvement of membrane glycosaminoglycans, the p28 peptide is also used to deliver other peptides to cancer cells. The p28 peptide’s aa terminal roles in reducing cell proliferation and boosting apoptotic activity. Azurin-p28 can affect pathways of cancer signaling. By lowering or blocking VEGFR2 tyrosine kinase activity and phosphorylation, p28 prevents the angiogenesis of null tumors. The p28 peptide prevent the binding of constitutional morphogenic protein (Cop1), which is one of E3 ubiquitin ligases, with the DBD of p53 protein, and by reduction of ubiquitination and proteasomal degradation of p53 protein, they lead to a higher post-translational level of p53. The p53 protein is a tumor suppressor that inhibits tumor cell proliferation, participates in apoptosis, and regulates target gene transcription. Mouse double minute 2 (Mdm2) E3 ubiquitin ligase regulates degradation of the p53 protein by binding to its N-terminal activation domain (TAD).
Results: Since p28 peptide interacts directly with p53 tumor suppressor protein, it can be considered as a peptide with anticancer potential. Information about the DBD-p28 complex can reveal the function of p28 in regulating the anticancer effect of p53 protein, as well as the need to design new drugs that maintain the anticancer function of p53. Because as a result of post-translational stabilization of p53 against stress signals, the amount of this protein increases, the transcription of genes responsible for DNA repair increases and apoptosis occurs. Therefore, it can prevent cancers.
Conclusion: In conclusion, bacterial peptide p28, which is derived from azurin protein of Pseudomonas aeruginosa, can be used as an antitumor peptide and anticancer drug.
Keywords: P28, Azurin protein, P53, Pseudomonas aeruginosa, cancer