Browsing by Subject "Prostate Cancer"
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Item Hematologic malignancies following external beam radiation therapy for localized prostate cancer(2010-10-01) Ojha, Rohit P.; Felini, Martha J.; Singh, Karan P.; Thertulien, RaymondOjha, Rohit P. Hematologic malignancies following external beam radiation therapy for localized prostate cancer. Doctor of Public Health (Epidemiology), December 2010, 88 pp., 6 tables, 2 illustrations, references, 96 titles. The incidence of hematologic malignancies following external beam radiation therapy (EBRT) among prostate cancer patients has received limited attention despite evidence that radiation has a role in leukemogenesis and myelomagenesis. Therefore, we investigated the effect of external beam radiation therapy on acute myeloid leukemia and myeloma incidence among prostate cancer patients. We utilized the Surveillance, Epidemiology, and End Results database to identify a cohort of men (n=168,612) with newly diagnosed prostate adenocarcinoma between January 1988 and December 2003. Cox proportional hazard regression was used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of acute myeloid leukemia and myeloma incidence following definitive therapy with EBRT alone, brachytherapy alone, or surgery alone compared to no definitive therapy. The cohort yielded 184 incident acute myeloid leukemia cases and 344 incident myeloma cases during 1,064,820 person-years of follow-up after prostate adenocarcinoma diagnosis. Patients treated with EBRT had a higher adjusted relative hazard of developing acute myeloid leukemia than patients treated with brachytherapy or surgery when each therapy group was compared to patients who were not treated with definitive therapy (EBRT: HR=2.05, 95% CI 1.29, 3.26; brachytherapy: HR=1.22, 95% CI 0.46, 3.22; surgery: HR=1.24, 95% CI 0.77, 1.98). Patients treated with EBRT, brachytherapy, or surgery did not have increased adjusted relative hazards of developing myeloma when each therapy group was compared to patients who were not treated with definitive therapy (EBRT: HR=0.97, 95% CI: 0.70, 1.35; brachytherapy: HR=0.60, 95% CI: 0.28, 1.33; surgery: HR=1.02, 95% CI: 0.75, 1.39). Our findings suggest that acute myeloid leukemia incidence is a greater concern for patients treated with EBRT than brachytherapy for localized or locally advanced prostate adenocarcinoma. However, our results indicate that neither EBRT nor brachytherapy increases the relative hazard of myeloma incidence among patients with localized or locally advanced prostate adenocarcinoma. Ultimately, our findings may contribute to the collective evidence regarding the risks and benefits of external beam radiation therapy.Item Novel Gene C17ORF37 in Prostate Cancer Progression and Metastasis(2010-05-01) Dasgupta, Subhamoy; Vishwanatha, Jamboor K.C17orf37 also known as MGC14832, C35, Rdx12, a novel gene located on human chromosome 17q12 in the ERBB2 amplicon, is abundantly expressed in different forms of human cancer. C17orf37 expression has been reported to positively correlate with grade and stage of cancer progression; however the functional significance of C17orf37 overexpression in cancer biology is not known. Here, we show that C17orf37 is highly expressed in prostate cancer cell lines and tumors, compared to minimal expression in normal prostate cells and tissues. RNA interference mediated downregulation of C17orf37 resulted in decreased migration and invasion of DU-145 prostate cancer cells, and suppressed the DNA binding activity of NF-κB transcription factor resulting in reduced expression of downstream target genes MMP-9, uPA and VEGF. Phosphorylation of PKB/Akt was also reduced upon C17orf37 downregulation, suggesting C17orf37 acts as a signaling molecule that increases invasive potential of prostate cancer cells by NF-κB mediated downstream target genes. Cellular localization studies by confocal and total internal reflection (TIRF) microscopy revealed expression of C17orf37 protein in the cytosol predominantly surrounding the membrane of prostate cancer cells. We identified that C17orf37 has a functional prenylation motif and is posttranslationally modified by geranylgeranyl transferase-I (GGTase-I) enzyme. Prenylated proteins (often referred to as CAAX family of proteins) contain a CAAX motif (C denotes cysteine, A represents aliphatic amino acids, and X any amino acid) at the carboxyl terminal which serves as a substrate for a series of post-translational modifications converting otherwise hydrophilic to lipidated proteins with hydrophobic domain, facilitating membrane localization. Geranylgeranylation of C17orf37 at the ‘CVIL’ motif translocates the protein to the inner leaflet of plasma membrane, enhances migratory phenotype of cells by inducing increased filopodia formation and potentiates directional migration. The prenylation-deficient C17orf37 mutant is functionally inactive and fails to disseminate injected cells in the mouse model of metastasis. This implies that prenylation activates the C17orf37 protein in cancer cells and functionally regulates metastatic progression of the disease. Our data strongly suggest C17orf37 overexpression in prostate cancer functionally enhances migration and invasion facilitating metastatic dissemination of tumor cells, and is an important target for cancer therapy.Item Synergy 2010: Annual Research Report(2010-01-01)Item TETRANDRINE INDUCES ROS-DRIVEN CASPASE-DEPENDENT APOPTOSIS OF PROSTATE CANCER CELLS VIA MITOCHONDRIAL AND CELL DEATH RECEPTOR PATHWAY(2014-03) Chaudhary, Pankaj; Vishwanatha, Jamboor K.Androgen deprivation is still the standard systemic therapy for prostate cancer, but patients invariably relapse with a more aggressive form of prostate cancer termed hormone refractory, androgen independent, or castration resistant prostate cancer. Once prostate cancer becomes castration-resistant, metastasis is a significant problem and treatment options are limited. Therefore, identification of novel agents that can selectively kill tumor cells with no additional toxicity to normal tissue would have significant impact on prostate cancer therapy. Purpose (a): Tetrandrine, a bisbenzylisoquinoline alkaloid, isolated from the root of Stephania tetrandra is used in traditional Chinese medicine as an anti-rheumatic, anti-inflammatory, and anti-hypertensive agent for the past several years. During recent years, increasing number of studies have focused on the potential of tetrandrine in cancer therapy. Despite its great potential as an anti-cancer agent, the effect of tetrandrine in prostate cancer has not been studied. Therefore, in the present study, we demonstrate the cytotoxic efficacy of tetrandrine in human androgen-independent prostate cancer cells, PC3 and DU145, and delineate the mechanism of this effect. Methods (b): Prostate cancer cell lines, PC3 and DU145, and normal prostate PWR-1E cells were cultured in ATCC recommended medium. The toxicity of tetrandrine was analyzed by MTT assay and Vybrant Apoptosis Assay Kit. Western blotting was used to detect the expression of proteins involved in apoptosis. Results (c): Our results indicate that tetrandrine selectively inhibits the growth of PC3 and DU145 cancer cells compared to normal prostate PWR-1E cells. Treatment of cancer cells with tetrandrine caused the upregulation of Fas and Bax, downregulation of Bcl-2, cleavage of Bid, and release of cytochrome c, which were accompanied by activation of caspases-9, -3 and -8 and subsequently poly(ADP-ribose) polymerase cleavage. Pre-incubation with caspase-8 inhibitor significantly blocked the tetrandrine-induced Bid cleavage, reduction in mitochondrial membrane potential, and activation of caspase 3, and cell death. Together, these results suggest that the mitochondrial pathway is primarily involved in tetrandrine-induced apoptosis. Additionally, our results demonstrated that tetrandrine-induced apoptosis was caused by the generation of reactive oxygen species (ROS) and most of the signaling effects were attenuated with the preincubation of cells with N-acetylcysteine, thereby further confirming the involvement of ROS in these events. Conclusions (d): Our results demonstrated that treatment of prostate cancer cells with tetrandrine induces caspase-dependent apoptosis via Fas-mediated Bid cleavage and cytochrome c release.