The New Anti-Tumor Mechanism of Malignant Mesothelioma Orphan Drug Onconase

Onconase, a ribonuclease from oocytes of Northern Leopard frogs (Rana pipiens), has been granted orphan-drug designation for the treatment of malignant mesothelioma in USA, European Union, and Australia. Mesothelioma is a rare form of cancer that develops from transformed cells originating in the mesothelium, which is usually caused by exposure to asbestos. The prognosis for malignant mesothelioma remains disappointing for lack of effective chemotherapy or other treatment strategies. Onconase specifically induces apoptosis of cancer cells but has low cytotoxicity to their normal counterparts; however, as an anti-cancer drug, the mechanisms of its antitumor activity are not well understood. Recently, a team of researchers, led by LIU Mofang, at Shanghai Institute of Biochemistry and Cell Biology (SIBCB), CAS, brought new insights into the mechanisms of Onconase-mediated cytotoxicity in malignant mesothelioma cells.

 

QIAO Meng, ZU Lidong, and their colleagues, under the supervision of Dr. LIU Mofang, studied the roles and mechanisms of Onconase to microRNAs (miRNAs) in mesothelioma cells. They found that Onconase ubiquitously reduces miRNA expression and subsequently increases the expression of their target genes in mesothelioma cells, revealing miRNAs as a novel class of RNA substrates for Onconase in cancer cells. Intriguingly, Onconase preferentially degrades miRNA precursors in stead of mature forms of miRNAs, thus reducing the amount of mature miRNAs produced from Dicer processing. Their results also indicate that Onconase predominantly cleaved miRNA precursors at UG and UU residues. Given the well-documented causal roles of miRNAs in cancers, the findings provided a new mechanism for the anti-tumor activity of Onconase in cancer cells.

 

This work entitled “Onconase down-regulates microRNA expression through targeting microRNA precursors” was published online in Cell Research on April 24^th , 2012, before its appearance in print.

 

This study was supported by grants from the Chinese Academy of Sciences, the Ministry of Science and Technology, National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.

 

AUTHOR CONTACT:

LIU Mofang

Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

Phone: 86-21-54921146; E-mail: mfliu@sibs.ac.cn