Related Experiment Videos
Antineoplastic ribonucleases selectively kill thyroid carcinoma cells via caspase-mediated induction of apoptosis
Daniela Spalletti-Cernia1, Rosanna Sorrentino, Sonia Di Gaetano
1Istituto 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.
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.
Insights
Dimeric ribonucleases (BS-RNase and HHP2-RNase) effectively induce apoptosis in human thyroid cancer cells by activating caspases and reducing survival signals. These findings highlight their potential as targeted therapies for aggressive thyroid cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Dimeric ribonucleases, such as bovine seminal ribonuclease (BS-RNase) and engineered human pancreatic ribonuclease (HHP2-RNase), exhibit potent antitumor properties.
- Monomeric RNase A lacks these significant antitumor effects.
Purpose of the Study:
- To investigate the mechanism by which dimeric ribonucleases induce apoptosis in human thyroid carcinoma cell lines.
- To evaluate the in vivo efficacy of BS-RNase in a preclinical model.
Main Methods:
- Treatment of human thyroid carcinoma cell lines with BS-RNase and HHP2-RNase.
- Analysis of caspase activation (caspase-8, -9, and -3) and poly(ADP-ribose) polymerase cleavage.
- Assessment of Akt/protein kinase B (PKB) phosphorylation.
- In vivo studies using nude mice xenograft models.
Main Results:
- BS-RNase and HHP2-RNase, but not monomeric RNase A, induced apoptosis in thyroid cancer cells.
- Apoptosis was mediated by the activation of caspase cascades and reduced Akt/PKB phosphorylation.
- BS-RNase demonstrated significant antitumor effects in vivo, associated with apoptosis and caspase activation.
Conclusions:
- Dimeric ribonucleases trigger apoptosis in thyroid cancer cells through caspase activation and inhibition of survival pathways.
- BS-RNase and HHP2-RNase show high selectivity for malignant cells, indicating their promise for aggressive thyroid cancer treatment.