Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is the most common malignancy of elderly men in the United States. Since there is no curative treatment for advanced prostate cancer, exploration of novel modalities of treatment is essential. Telomerase, a ribonucleoprotein, is detected in the vast majority of prostate cancer, but not in normal or benign prostatic hyperplasia tissues. Thus, telomerase is expected to be a very strong candidate for targeted therapy of prostate cancer. In this study, we synthesized a 19-mer antisense oligonucleotide against the RNA component of human telomerase (hTR) linked to a 2-5A molecule (2-5A-anti-hTR) and examined its cytotoxic effect on prostate cancer cells. The 2-5A antisense strategy relies on the recruitment and activation of RNase L at the site of targeted RNA sequence. We here show that treatment with 2-5A-anti-hTR in the presence of a cationic liposome reduced cell viability of tumor cell lines tested to 9-18% within 6 days. In contrast, normal fibroblast cells were resistant to the treatment. Its effect was mainly due to induction of apoptosis by activated caspase family members. Furthermore, treatment of subcutaneous tumors in nude mice with 2-5A-anti-hTR significantly suppressed the tumor growth through induction of apoptosis (P<0.001). The treatment with 2-5A-anti-hTR may be a promising strategy for the treatment modality of prostate cancer with telomerase activity.
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PMID:Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component. 1082 70

Prostate cancer is the second leading cause of cancer-related deaths in the United States. However, the underlying molecular events for prostate cancer development are not clear. In this study, we applied the recently developed technology known as differential subtraction chain (DSC) to identify a novel gene whose expression is inactivated in high grade prostate cancer. This gene, designated as SAPC, is expressed in normal prostate acinar cells. Its expression is dramatically down-regulated in high grade prostate cancers (4/4) but is unaltered in low grade prostate cancers. It encodes a 7.7-kd protein. Its sequence shares some homology with the cysteine-rich domain of 2-5A-dependent RNase L, which is a critical component of the interferon-induced apoptosis cascade. The selective inactivation in the more aggressive prostate cancers holds promise for SAPC as a potential prognostic marker for high grade prostate cancer.
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PMID:Identification of a novel gene with increasing rate of suppression in high grade prostate cancers. 1114 74

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.
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PMID:Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. 1179 94

Recently, the interferon (IFN) antiviral pathways and prostate cancer genetics and have surprisingly converged on a single-strand specific, regulated endoribonuclease. Genetics studies from several laboratories in the U.S., Finland, and Israel, support the recent identification of the RNase L gene, RNASEL, as a strong candidate for the long sought after hereditary prostate cancer 1 (HPC1) allele. Results from these studies suggest that mutations in RNASEL predispose men to an increased incidence of prostate cancer, which in some cases reflect more aggressive disease and/or decreased age of onset compared with non-RNASEL linked cases. RNase L is a uniquely regulated endoribonuclease that requires 5'-triphosphorylated, 2',5'-linked oligoadenylates (2-5A) for its activity. The presence of both germline mutations in RNASEL segregating with disease within HPC-affected families and loss of heterozygosity (LOH) in tumor tissues suggest a novel role for the regulated endoribonuclease in the pathogenesis of prostate cancer. The association of mutations in RNASEL with prostate cancer cases further suggests a relationship between innate immunity and tumor suppression. It is proposed here that RNase L functions in counteracting prostate cancer by virtue of its ability to degrade RNA, thus initiating a cellular stress response that leads to apoptosis. This monograph reviews the biochemistry and genetics of RNase L as it relates to the pathobiology of prostate cancer and considers implications for future screening and therapy of this disease.
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PMID:Implications for RNase L in prostate cancer biology. 1259 May 67

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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PMID:Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. 1458 76

Adenosine deaminase (ADA) is expressed intracellularly by all cells, but in some tissues, it is also associated with the cell surface multifunctional glycoprotein CD26/dipeptidyl peptidase IV. By modulating extracellular adenosine, this "ecto-ADA" may regulate adenosine receptor signaling implicated in various cellular functions. CD26 is expressed on the surface of human prostate cancer 1-LN cells acting as a receptor for plasminogen (Pg). Since ADA and Pg bind to CD26 at distinct but nearby sites, we investigated a possible interaction between these two proteins on the surface of 1-LN cells. Human ADA binds to CD26 on the surface 1-LN cells and immobilized CD26 isolated from the same cells with similar affinity. In both cases, ADA binding is diminished by mutation of ADA residues known to interact with CD26. ADA was also found to bind Pg 2 in the absence of CD26 via the Pg kringle 4 (K4) domain. In the presence of 1-LN cells or immobilized CD26, exogenous ADA enhances conversion of Pg 2 to plasmin by 1-LN endogenous urinary plasminogen activator (u-PA), as well as by added tissue Pg Activator (t-PA), suggesting that ADA and Pg bind simultaneously to CD26 in a ternary complex that stimulates the Pg activation by its physiologic activators. Consistent with this, in melanoma A375 cells that bind Pg, but do not express CD26, the rate of Pg activation was not affected by ADA. Thus, ADA may be a factor regulating events in prostate cancer cells that occur when Pg binds to the cell surface and is activated.
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PMID:Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells. 1501 24

Several genetic loci are suspected to be involved in hereditary prostate cancer, including the hereditary prostate cancer 1 (HPC1) locus at chromosome 1q24-25. The ribonuclease L (RNase L) gene has been reported as the putative hereditary prostate cancer gene located at HPC1. If this is the case, mutations of RNase L should be found at a greater frequency in familial cancers than in sporadic prostate cancers. Examination of familial and sporadic cases of prostate cancer by polymerase chain reaction and DNA sequencing resulted in a mutational frequency rate that was not statistically different between the 2 forms of the disease. These results suggest that the mutations examined within this study are rare and may contribute to very few familial prostate cancers.
Clin Prostate Cancer 2003 Dec
PMID:Mutations in ribonuclease L gene do not occur at a greater frequency in patients with familial prostate cancer compared with patients with sporadic prostate cancer. 1504 Aug 62

The hereditary prostate cancer 1 (HPC1) allele maps to the RNASEL gene encoding a protein (RNase L) implicated in the antiviral activity of interferons. To investigate the possible role of RNase L in apoptosis of prostate cancer cells, we decreased levels of RNase L by severalfold in the DU145 human prostate cancer cell line through the stable expression of a small interfering RNA (siRNA). Control cells expressed siRNA with three mismatched nucleotides to the RNase L sequence. Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A). Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)]. In contrast, cells expressing siRNA to the RNase L inhibitor RLI (HP68) showed enhanced apoptosis in response to Topo I inhibitor alone or in combination with TRAIL. An inhibitor of c-Jun NH(2)-terminal kinases reduced apoptosis induced by treatment with either 2-5A or the combination of camptothecin and TRAIL, thus implicating c-Jun NH(2)-terminal kinase in the apoptotic signaling pathway. Furthermore, prostate cancer cells were sensitive to apoptosis from the combination of 2-5A with either TRAIL or Topo I inhibitor, whereas normal prostate epithelial cells were partially resistant to apoptosis. These findings indicate that RNase L integrates and amplifies apoptotic signals generated during treatment of prostate cancer cells with 2-5A, Topo I inhibitors, and TRAIL.
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PMID:HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. 1560 85

To date, germline mutations have been found in three candidate genes for hereditary prostate cancer: ELAC2 at 17p11, RNASEL at 1q25 and MSR1 at 8p22. RNASEL, encoding the 2',5'-oligoadenylate-dependant RNase L, seems to have rare mutations in different ethnicities, such as M1I in Afro-Americans, E265X in men of European descent and 471delAAAG in Ashkenazi Jews. In order to evaluate the relevance of RNASEL in the German population, we sequenced its open reading frame to determine the spectrum and frequency of germline mutations. The screen included 303 affected men from 136 Caucasian families, of which 45 met the criteria for hereditary prostate cancer. Variants were analysed using a family-based association test, and genotyped in an additional 227 sporadic prostate cancer patients and 207 controls. We identified only two sib pairs (1.4% of our families) cosegregating conspicuous RNASEL variants with prostate cancer: the nonsense mutation E265X, and a new amino-acid substitution (R400P) of unknown functional relevance. Both alleles were also found at low frequencies (1.4 and 0.5%, respectively) in controls. No significant association of polymorphisms (I97L, R462Q and D541E) was observed, neither in case-control analyses nor by family-based association tests. In contrast to previous reports, our study does not suggest that common variants (i.e. R462Q) modify disease risk. Our results are not consistent with a high penetrance of deleterious RNASEL mutations. Due to the low frequency of germline mutations present in our sample, RNASEL does not have a significant impact on prostate cancer susceptibility in the German population.
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PMID:Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. 1571 8

Inhibition of protein synthesis by interferon treatment is mediated by two major pathways: the 2'-5'-linked oligoadenylates [2-5 (A)] synthetase-RNase L pathway and the double-stranded ribonucleic acid-dependent protein kinase-mediated pathway. 2-5 (A) synthetases are unique interferon-inducible enzymes that, upon activation by double-stranded RNA, polymerize adenosine triphosphate (ATP) to 2-5 (A) synthases. These 2-5 (A) synthetases bind and activate the latent RNase L, causing RNA degradation. In addition to the three major size classes of enzymatically active oligoadenylate synthetase proteins, at least one inactive oligoadenylate synthetase is known in human and mouse. Structure-function studies and recent crystal structure determination have identified several distinct sites in these proteins responsible for different biochemical functions. RNase L is the only known protein that binds to 2-5 (A) synthetases with very high affinity. Gene knockout studies of RNase L have identified its role in antiviral actions of interferon and in apoptosis. Recently, it has also been implicated in prostate cancer metastasis. In this chapter we describe several methodologies for studying biochemical and physiological properties of the 2-5 (A) synthetase-RNase L pathway.
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PMID:Assays for the interferon-induced enzyme 2',5' oligoadenylate synthetases. 1600 Aug 56


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