Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

Our plain-English summary of Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs, by G. Gotte, M. Menegazzi (Frontiers in Immunology, 2019).

The study

• Authors: G. Gotte, M. Menegazzi
• Journal: Frontiers in Immunology
• Published: 2019;10:2626
• Type of article: Review
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Ribonucleases (RNases) are a large number of enzymes gathered into different bacterial or eukaryotic superfamilies. Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family. In physiological conditions, most RNases secreted in the extracellular space counteract the undesired effects of extracellular RNAs and become protective against infections. Instead, if they enter the cell, RNases can digest intracellular RNAs, becoming cytotoxic and having advantageous effects against malignant cells. Their biological activities have been investigated either in vitro, toward a number of different cancer cell lines, or in some cases in vivo to test their potential therapeutic use. However, immunogenicity or other undesired effects have sometimes been associated with their action. Nevertheless, the use of RNases in therapy remains an appealing strategy against some still incurable tumors, such as mesothelioma, melanoma, or pancreatic cancer. The RNase inhibitor (RI) present inside almost all cells is the most efficacious sentry to counteract the ribonucleolytic action against intracellular RNAs because it forms a tight, irreversible and enzymatically inactive complex with many monomeric RNases. Therefore, dimerization or multimerization could represent a useful strategy for RNases to exert a remarkable cytotoxic activity by evading the interaction with RI by steric hindrance. Indeed, the majority of the mentioned RNases can hetero-dimerize with antibody derivatives, or even homo-dimerize or multimerize, spontaneously or artificially. This can occur through weak interactions or upon introducing covalent bonds. Immuno-RNases, in particular, are fusion proteins representing promising drugs by combining high target specificity with easy delivery in tumors. The results concerning the biological features of many RNases reported in the literature are described and discussed in this review. Furthermore, the activities displayed by some RNases forming oligomeric complexes, the mechanisms driving toward these supramolecular structures, and the biological rebounds connected are analyzed. These aspects are offered with the perspective to suggest possible efficacious therapeutic applications for RNases oligomeric derivatives that could contemporarily lack, or strongly reduce, immunogenicity and other undesired side-effects.

Copyright © 2019 Gotte and Menegazzi.

In plain English

This was a review article; the authors surveyed published work on secretory ribonucleases (RNases) and on ways of oligomerizing them to design antitumor drugs. They described the pancreatic-type superfamily, which includes bovine RNase A, the natively dimeric bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5) and the amphibian onconase (ranpirnase); of the eight human secretory variants, the eosinophil-derived RNase 2 and RNase 3 were placed outside that superfamily, while barnase and binase were placed in the bacterial RNase N1/T1 family. Roles of secreted RNases in clearing extracellular RNA, immune modulation and antimicrobial defence were reviewed. The review set out the steps an RNase must pass to kill a cell: membrane interaction, endocytosis, intracellular routing, and escape from the cytosolic ribonuclease inhibitor (RI). It reported that onconase evades RI because it lacks the key residues for a tight complex, and that BS-RNase cytotoxicity was attributed only to its N-swapped isoform. Covalent cross-linking, antibody fusion (immuno-RNases) and non-covalent three-dimensional domain swapping were reviewed; an onconase dimer was reported as more cytotoxic to pancreatic cancer cells than the monomer, while findings for RNase A oligomers were called controversial.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: review article (narrative review of published literature on secretory RNases and their oligomers)
• Who was studied: No human population; the review covered laboratory studies of secretory RNases of bovine, human, amphibian and bacterial origin, tested in cancer cell lines and in some cases in mice
• Exposure: Not an exposure study; the agents reviewed were RNases and their derivatives (RNase A, BS-RNase, human RNase 1, angiogenin/RNase 5, onconase, barnase, binase) and their covalent cross-linked oligomers, immuno-RNase fusion proteins and non-covalent domain-swapped oligomers
• Main results:
  • The review reported that onconase (ONC) escapes the cytosolic ribonuclease inhibitor because it lacks the residues needed for a tight RNase-RI complex
  • Cytotoxicity of bovine seminal RNase was reported to come only from its N-swapped dimeric isoform, not from the unswapped isoform or the monomer
  • An onconase N-swapped dimer obtained by lyophilization from acetic acid was reported to be more cytotoxic to pancreatic cancer cells than native monomeric onconase
  • Results reviewed for the antitumor activity of RNase A oligomers were described as controversial (active against leukemia cells in vitro and transplanted human melanoma in nude mice, but not against two human pancreatic tumor cell lines)
  • Monomeric wild-type onconase was reported to have given positive in vitro and in vivo results against several tumors, including pleural mesothelioma
  • Renal toxicity of onconase seen in clinical trials was described as reversible
  • The eosinophil variants RNase 2 and RNase 3 were reported to fall outside the pancreatic-type superfamily
• The authors' conclusion: The authors concluded that dimerization or more extensive oligomerization of RNases, including immuno-RNase fusion proteins and domain-swapped oligomers, may be a useful strategy for antitumor drug design, but that improvements in cytotoxicity, half-life and side-effects are still needed
• Limitations the authors state:
  • The authors stated that the actual antitumor potential of RNase A species still needs further investigation
  • The authors stated that the antitumor activity of the dimerizing RNase 1 variants has not been studied
  • The authors stated that the biological activities of the bacterial variants balnase and balifase have not been sufficiently investigated

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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