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

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.

RNase A Domain-Swapped Dimers Produced Through Different Methods: Structure–Catalytic Properties and Antitumor Activity

“…In any case, the significant anti-tumor activity exerted by the N-dimers in both human MeWo and A375 melanoma cell lines, as well as the activity of C-dimers vs. A375 cells, can represent a seed to develop new non mutagenic therapies to counteract with pt-RNases tumors that are presently still incurable [ 65 ].…”

The Tumor Suppressor TGFBR3 Blocks Lymph Node Metastasis in Head and Neck Cancer

“…ANG is a small ribonuclease. The cellular function of ANG is intriguing and largely attributes to its ability to transactivate ribosomal RNA in the nucleoli and tRNA cleavage activity [41]. Notably, it was recently demonstrated that ANG binds to its receptor Plexin-B2 and exerts mitogenic activity through multiple kinase pathways that include ERK, AKT, and RAC [42].…”

“…Thus, ANG could function in cell membrane, cytosol, and nucleoli. Moreover, modification of ANG affects its cellular activity [41]. These properties may partly explain why ANG has cytotoxic or proliferative activities, depending on the contexts and cell types [43,44].…”

Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents

“…Secretory RNases are a vast group of enzymes that were initially considered as mere non-specific degradative proteins and that today are known to participate in a wide spectrum of biological activities (a very well-described review of these activities has been recently provided by Gotte and Menegazzi [ 5 ]). These RNases, found in eukaryotic and prokaryotic organisms, are secreted or accumulate inside cellular structures associated with secretory pathways, and therefore they can be found in spaces that are not normally associated with the presence of RNA.…”