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

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

Research output: Contribution to journalArticle

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 LR462Q activity was correlated with a reduction in its ability to dimerize into a catalytically active form. Furthermore, RNase LR462Q 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.

Original languageEnglish (US)
Pages (from-to)6795-6801
Number of pages7
JournalCancer Research
Volume63
Issue number20
StatePublished - Oct 15 2003

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Prostatic Neoplasms
Apoptosis
Ribonucleases
Mutation
Cell Line
Sequence Deletion
Antiviral Agents
2-5A-dependent ribonuclease
2',5'-oligoadenylate
Alleles
Enzymes
Genes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Xiang, Y., Wang, Z., Murakami, J., Plummer, S., Klein, E. A., Carpten, J. D., ... Silverman, R. H. (2003). Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2′,5′-Oligoadenylates. Cancer Research, 63(20), 6795-6801.

Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2′,5′-Oligoadenylates. / Xiang, Ying; Wang, Zhengfu; Murakami, Junko; Plummer, Sarah; Klein, Eric A.; Carpten, John D.; Trent, Jeffrey M.; Isaacs, William B; Casey, Graham; Silverman, Robert H.

In: Cancer Research, Vol. 63, No. 20, 15.10.2003, p. 6795-6801.

Research output: Contribution to journalArticle

Xiang, Y, Wang, Z, Murakami, J, Plummer, S, Klein, EA, Carpten, JD, Trent, JM, Isaacs, WB, Casey, G & Silverman, RH 2003, 'Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2′,5′-Oligoadenylates', Cancer Research, vol. 63, no. 20, pp. 6795-6801.
Xiang Y, Wang Z, Murakami J, Plummer S, Klein EA, Carpten JD et al. Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2′,5′-Oligoadenylates. Cancer Research. 2003 Oct 15;63(20):6795-6801.
Xiang, Ying ; Wang, Zhengfu ; Murakami, Junko ; Plummer, Sarah ; Klein, Eric A. ; Carpten, John D. ; Trent, Jeffrey M. ; Isaacs, William B ; Casey, Graham ; Silverman, Robert H. / Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2′,5′-Oligoadenylates. In: Cancer Research. 2003 ; Vol. 63, No. 20. pp. 6795-6801.
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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 LR462Q activity was correlated with a reduction in its ability to dimerize into a catalytically active form. Furthermore, RNase LR462Q 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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