Antineoplastic ribonucleases selectively kill thyroid carcinoma cells via caspase-mediated induction of apoptosis.
Bovine seminal ribonuclease (BS-RNase), a natural dimeric homolog of bovine pancreatic RNase (RNase A), and HHP2-RNase, an engineered dimeric form of human pancreatic RNase (HP-RNase), are endowed with powerful antitumor effects. Here we show that BS- and HHP2-RNases, but not monomeric RNase A, induce apoptosis of human thyroid carcinoma cell lines. RNase-induced apoptosis was associated with activation of initiation caspase-8 and -9. This was followed by activation of executioner caspase-3, leading to the proteolytic cleavage of poly(ADP-ribose) polymerase. The caspase inhibitor Z-Val-Ala-Asp-(OMe)-fluoromethylketone protected thyroid cancer cells from BS-RNase-induced apoptosis. RNase-triggered apoptosis and caspase activation were accompanied by reduced phosphorylation of Akt/protein kinase B (PKB), a serine-threonine kinase that when phosphorylated is able to deliver survival signals to cancer cells. BS-RNase antitumor effects in nude mice were accompanied by caspase activation and apoptosis. Because of the high selectivity of apoptotic effects for malignant cells, BS- and HHP2-RNase are promising tools for the treatment of aggressive thyroid cancer.
Spalletti-Cernia
Daniela
D
Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, 80131 Naples, Italy.
Sorrentino
Rosanna
R
Di Gaetano
Sonia
S
Arciello
Angela
A
Garbi
Corrado
C
Piccoli
Renata
R
D'Alessio
Giuseppe
G
Vecchio
Giancarlo
G
Laccetti
Paolo
P
Santoro
Massimo
M
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000503:physiopathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004722:Endoribonucleases / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012259:Ribonuclease, Pancreatic / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000503:physiopathology*; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D011518:Proto-Oncogene Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D004722:Endoribonucleases; C032523:ribonuclease SPL; D012259:Ribonuclease, Pancreatic; C475035:pancreatic RNase 2, human; D020169:Caspases