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Antineoplastic Ribonucleases Selectively Kill Thyroid Carcinoma Cells Via Caspase-Mediated Induction of Apoptosis

Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche (CNR), Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II (D.S.-C., R.S., C.G., G.V., M.S.), 80131 Naples, Italy; Dipartimento di Chimica Biologica, Università di Napoli Federico II (S.D.G., A.A., R.P., G.D., P.L.), 80134 Naples, Italy; and Istituto di Biostrutture e Bioimmagini-CNR (S.D.G.), 80134 Naples, Italy

Address all correspondence and requests for reprints to: Dr. Massimo Santoro, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Via S. Pansini 5, 80131 Naples, Italy. E-mail: masantor{at}unina.it.

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.

This work was supported by the Associazione Italiana per la Ricerca sul Cancro; the Italian Ministry of Instruction, University, and Research; the Italian Ministry of Health; and a fellowship from the European Community-European Social Fund-FSE (to D.S.C.).

D.S.-C. and R.S. are recipients of a fellowship from the BioGeM scar.l. (Biotecnologia e Genetica Molecolare nel Mezzogiorno d’Italia) Consortium.

Abbreviations: BS-, Bovine seminal; cRI, cytosolic ribonuclease inhibitor; fmk, fluoromethylketone; HDF, human diploid fibroblasts; HP-, human pancreatic; PARP, poly(ADP-ribose) polymerase; PI3K, phosphoinositide 3-kinase; pNA, p-nitroanilide; RNase, ribonuclease; zVADfmk, Z-Val-Ala-Asp-(OMe)-fluoromethylketone; Akt/PKB, protein kinase B.

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