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.
Antineoplastic ribonucleases selectively kill thyroid carcinoma cells via caspase-mediated induction of apoptosis / SPALLETTI CERNIA, D; Sorrentino, R; DI GAETANO, S; Arciello, Angela; Garbi, Corrado; Piccoli, Renata; D'Alessio, Giuseppe; Vecchio, Giancarlo; Laccetti, Paolo; Santoro, Massimo. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - STAMPA. - 88:6(2003), pp. 2900-2907. [10.1210/jc.2002-020373]
Antineoplastic ribonucleases selectively kill thyroid carcinoma cells via caspase-mediated induction of apoptosis
ARCIELLO, ANGELA;GARBI, CORRADO;PICCOLI, RENATA;D'ALESSIO, GIUSEPPE;VECCHIO, GIANCARLO;LACCETTI, PAOLO;SANTORO, MASSIMO
2003
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.