Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates.

Abstract

The RNASEL gene, a strong candidate for the hereditary prostate cancer 1 allele (HPC1), encodes a single-stranded specific endoribonuclease involved in the antiviral actions of IFNs. RNase L is activated enzymatically after binding to unusual 5'-phosphorylated, 2',5'-linked oligoadenylates (2-5A). Biostable phosphorothioate analogues of 2-5A were synthesized chemically and used to study the effects of naturally occurring mutations and polymorphisms in RNASEL. The 2-5A analogues induced RNase L activity and caused apoptosis in cultures of late-stage, metastatic human prostate cancer cell lines DU145, PC3, and LNCaP. However, DU145 and PC3 cells were more sensitive to 2-5A than LNCaP cells, which are heterozygous for an inactivating deletion mutation in RNase L. The RNase activities of missense variants of human RNase L were compared after expression in a mouse RNase L(-/-) cell line. Several variants (G59S, I97L, I220V, G296V, S322F, Y529C, and D541E) produced similar levels of RNase L activity as wild-type enzyme. In contrast, the R462Q variant, previously implicated in up to 13% of unselected prostate cancer cases, bound 2-5A at wild-type levels but had a 3-fold decrease in RNase activity. The deficiency in RNase L(R462Q) activity was correlated with a reduction in its ability to dimerize into a catalytically active form. Furthermore, RNase L(R462Q) was deficient in causing apoptosis in response to 2-5A consistent with its possible role in prostate cancer development. Our findings support the notion that RNASEL mutations and some variants allow tumor cells to escape a potent apoptotic pathway.

• Authors: Ying Xiang, Zhengfu Wang, Junko Murakami, Sarah Plummer, Eric A Klein, John D Carpten, Jeffrey M Trent, William B Isaacs, Graham Casey, Robert H Silverman
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 20 Pg. 6795-801 (Oct 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14583476 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenine Nucleotides
• Oligoribonucleotides
• 2',5'-oligoadenylate
• Endoribonucleases
• 2-5A-dependent ribonuclease

Topics

• Adenine Nucleotides (pharmacology)
• Apoptosis (drug effects, genetics)
• Bone Neoplasms (secondary)
• Brain Neoplasms (secondary)
• Cell Line, Tumor
• Dimerization
• Endoribonucleases (genetics)
• Enzyme Activation (drug effects)
• Humans
• Lymphatic Metastasis
• Male
• Mutation, Missense
• Oligoribonucleotides (pharmacology)
• Prostatic Neoplasms (drug therapy, enzymology, genetics, pathology)