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Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2',5'-Oligoadenylates¹

Department of Cancer Biology, Lerner Research Institute [Y. X., Z. W., J. M., S. P., G. C., R. H. S.], and Urological Institute [E. A. K.], Cleveland Clinic Foundation, Cleveland, Ohio 44195; Translational Genomics Research Institute, Phoenix, Arizona 85004 [J. D. C., J. M. T.]; and Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287 [W. B. I.]

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.

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