Bovine seminal ribonuclease triggers Beclin1-mediated autophagic cell death in pancreatic cancer cells.

Abstract

Among the large number of variants belonging to the pancreatic-type secretory ribonuclease (RNase) superfamily, bovine pancreatic ribonuclease (RNase A) is the proto-type and bovine seminal RNase (BS-RNase) represents the unique natively dimeric member. In the present manuscript, we evaluate the anti-tumoral property of these RNases in pancreatic adenocarcinoma cell lines and in nontumorigenic cells as normal control. We demonstrate that BS-RNase stimulates a strong anti-proliferative and pro-apoptotic effect in cancer cells, while RNase A is largely ineffective. Notably, we reveal for the first time that BS-RNase triggers Beclin1-mediated autophagic cancer cell death, providing evidences that high proliferation rate of cancer cells may render them more susceptible to autophagy by BS-RNase treatment. Notably, to improve the autophagic response of cancer cells to BS-RNase we used two different strategies: the more basic (as compared to WT enzyme) G38K mutant of BS-RNase, known to interact more strongly than wt with the acidic membrane of cancer cells, or BS-RNase oligomerization (tetramerization or formation of larger oligomers). Both mutant BS-RNase and BS-RNase oligomers potentiated autophagic cell death as compared to WT native dimer of BS-RNase, while the various RNase A oligomers remained completely ineffective. Altogether, our results shed more light on the mechanisms lying at the basis of BS-RNase antiproliferative effect in cancer cells, and support its potential use to develop new anti-cancer strategies.

• Authors: Claudia Fiorini, Giovanni Gotte, Federica Donnarumma, Delia Picone, Massimo Donadelli
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1843 Issue 5 Pg. 976-84 (May 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24487065 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• Ribonuclease, Pancreatic

Topics

• Adenocarcinoma (pathology)
• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (physiology)
• Autophagy (drug effects, physiology)
• Beclin-1
• Cattle
• Cell Line, Tumor
• Male
• Membrane Proteins (physiology)
• Pancreatic Neoplasms (pathology)
• Ribonuclease, Pancreatic (pharmacology)
• Semen (enzymology)