-
Ayal A Aizer,
Jonathan J Paly,
Anthony L Zietman,
Paul L Nguyen,
Clair J Beard,
Sandhya K Rao,
Irving D Kaplan,
Andrzej Niemierko,
Michelle S Hirsch,
Chin-Lee Wu, Aria F Olumi,
M Dror Michaelson,
Anthony V D'Amico,
Jason A Efstathiou
[show abstract]
[hide abstract]
ABSTRACT: Multidisciplinary clinics offer a unique approach to the management of patients with cancer. Yet, limited data exist to show that such clinics affect management. The purpose of this study was to determine whether consultation at a multidisciplinary clinic is associated with selection of active surveillance in patients with low-risk prostate cancer.
The study comprised 701 men with low-risk prostate cancer managed at three tertiary care centers in Boston, MA in 2009. Patients either obtained consultation at a multidisciplinary prostate cancer clinic, at which they were seen by a combination of urologic, radiation, and medical oncologists in a concurrent setting, or they were seen by individual practitioners in sequential settings. The primary outcome was selection of active surveillance.
Crude rates of selection of active surveillance in patients seen at a multidisciplinary clinic were double that of patients seen by individual practitioners (43% v 22%), whereas the proportion of men treated with prostatectomy or radiation decreased by approximately 30% (P < .001). On multivariate logistic regression, older age (odds ratio [OR], 1.09; 95% CI, 1.05 to 1.12; P < .001), unmarried status (OR, 1.66; 95% CI, 1.01 to 2.72; P = .04), increased Charlson comorbidity index (OR, 1.37; 95% CI, 1.06 to 1.77; P = .02), fewer positive cores (OR, 0.92; 95% CI, 0.90 to 0.94; P < .001), and consultation at a multidisciplinary clinic (OR, 2.15; 95% CI, 1.13 to 4.10; P = .02) were significantly associated with pursuit of active surveillance.
Multidisciplinary care is associated with increased selection of active surveillance in men with low-risk prostate cancer. This finding may have an important clinical, social, and economic impact.
Journal of Clinical Oncology 07/2012; 30(25):3071-6. · 18.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 2005 International Society of Urological Pathology (ISUP) Consensus Conference modified the Gleason grading system for prostate cancer. In the modified criteria, ill-defined glands with poorly formed lumina and large cribriform glands with smooth borders, classically described as Gleason pattern 3 adenocarcinoma, were redefined as Gleason pattern 4. To evaluate the clinical outcome of patients upgraded by the ISUP criteria, the histologic slides of 1240 consecutive radical prostatectomy specimens at a single institution were reviewed, and each case of adenocarcinoma was graded on the basis of the original and modified Gleason criteria. A total of 806 patients with prostate cancer of classical Gleason score 3+3=6 or 3+4=7 and modified Gleason score 6 to 8 were analyzed with a median overall follow-up of 12.6 years. In the study population, 34% of patients with classical Gleason score 3+3=6 prostate cancer were upgraded to modified Gleason score 7 or 8 by the ISUP criteria. Compared to patients with modified Gleason score 3+3=6 and patients with classical Gleason score 3+4=7, the upgraded patients were at intermediate risk for biochemical progression (paired log-rank P≤0.003) and metastasis (paired log-rank P≤0.04) after radical prostatectomy. The hazard ratio for upgrading was 1.60 (95% confidence interval, 1.09-2.35, P=0.02) for biochemical recurrence and 5.02 (95% confidence interval, 1.77-14.2, P=0.003) for metastasis. These results validate the prognostic value of the modified Gleason grading system and suggest that the recognition of an intermediate-risk histological pattern may be useful in the prognosis of patients with prostate cancer.
The American journal of surgical pathology 06/2012; 36(6):838-43. · 4.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The term close surgical margin refers to a tumor extending to the inked margin of the specimen without reaching it. Current guidelines state that a close surgical margin should simply be reported as negative. However, this recommendation remains controversial and relies on limited evidence. We evaluated the impact of close surgical margins on the long-term risk of biochemical recurrence after radical prostatectomy.
We identified 1,195 consecutive patients who underwent radical prostatectomy and lymphadenectomy for localized prostate cancer at our institution from 1993 to 1999. In 894 of these patients associations between margin status and location, Gleason score, pathological stage, preoperative prostate specific antigen, prostate weight and age with the risk of biochemical recurrence were examined.
Of these 894 patients 644 (72%) had negative margins and of these patients 100 (15.5%) had close surgical margins. In the group with prostate specific antigen failure, median time to recurrence was 3.5 years. In the group without recurrence median followup was 9.9 years. Cumulative recurrence-free survival differed significantly among positive, negative and close surgical margins (p <0.001). On multivariate analysis a close surgical margin constituted a significant, independent predictor of recurrence (HR 2.1, 95% CI 1.04-4.33). Gleason score and positive margins were the strongest prognostic factors.
In this cohort close surgical margins were independently associated with a twofold risk of postoperative biochemical recurrence. Further evaluation of the clinical significance of close surgical margins is indicated as they might be an indicator of local recurrence and of relevance when considering salvage therapy.
The Journal of urology 05/2012; 188(1):91-7. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: Gleason score is important for prostate cancer (CaP) risk stratification and prognostication but has a significant rate of upgrading. We examined the effect of prostate size and age on upgrading of Gleason 6 CaP. MATERIALS AND METHODS: A retrospective review was performed of patients with Gleason 6 CaP who underwent radical prostatectomy from 2001 through 2010. Preoperative clinical and pathologic variables were assessed to determine association with risk of upgrading at prostatectomy. RESULTS: A total of 1,836 patients were identified with Gleason 6 on prostate biopsy. Upgrading was observed in 543 (29.6%) patients with a final Gleason score of 3+4 in 463 (25.2%), 4+3 in 49 (2.7%), and 8-10 in 31 (1.7%). On univariate logistic regression, age, prostate weight, and PSA were significant predictors of Gleason score upgrading and remained significant on multiple logistic regression. Prostate weight was inversely related to risk of upgrading. To further explore this effect, we performed multiple logistic regression to examine risk of Gleason 6, 7, or 8-10 disease in 2,493 patients with Gleason 6-10 at prostatectomy. After controlling for age and PSA, there was a progressively increased risk of Gleason 6, 7, and 8-10 disease with decreasing prostate weight. CONCLUSIONS: Older age, higher PSA, and smaller prostate gland size are associated with increased risk of Gleason score upgrading. The inverse relationship of prostate weight to risk of Gleason upgrading may be related to increased high-grade disease in smaller glands.
Urologic Oncology 12/2011; · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH.
Differentiation 04/2011; 82(4-5):261-71. · 2.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To define the role of positive surgical margins (PSMs) after radical retropubic prostatectomy as a predictor of biochemical failure (BCF) in prostate cancer with respect to pathologic stage.
A retrospective cohort study of 300 patients who had undergone radical retropubic prostatectomy from 1993 to 1995 was performed. The role of margin status and the length of the PSM in the progression to BCF was defined after controlling for the preoperative prostate-specific antigen level, Gleason score, tumor stage, tumor volume, seminal vesical invasion, lymphovascular invasion, and perineural invasion using a multivariate regression model. The median follow-up time was 12 years.
The presence of PSMs correlated with a shorter time to BCF in men with Stage pT2 disease (P<.0001) but not in men with Stage pT3 disease (P=.66). Of the patients with Stage pT2 disease and PSMs, the PSM length did not correlate with progression to BCF. PSMs predicted a shorter time to progression to BCF in patients with high- and low-volume pT2 disease (P=.0261 and P=.0003, respectively). Only PSMs predicted a shorter time to BCF on multivariate analysis in patients with Stage pT2 cancer (hazard ratio 2.33, 95% confidence interval 1.495-3.723). In patients with Stage pT3 disease, PSMs were not associated with an increased risk of BCF (hazard ratio 0.747, 95% confidence interval 0.328-1.703).
Surgical margin status did not affect the risk of BCF in patients with Stage pT3a disease; however, it did affect patients with Stage pT2 disease, irrespective of PSM length or disease volume. During 12 years of follow-up, the patients with PSMs and Stage pT2 disease had a risk of BCF similar to that of the patients with Stage pT3 disease.
Urology 03/2011; 78(1):121-5. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 5-α reductase 2 (5-AR 2) is a key enzyme that is responsible of proper development of prostate tissue. Inhibition of 5-AR 2 has proven to be efficacious for management of urinary symptoms secondary benign prostatic hyperplasia (BPH). However, some patients are resistant to the therapeutic effects of 5-AR 2 inhibitor. We wished to determine why some benign non-cancerous adult human prostates do not express 5-AR 2, and hypothesized that methylation of 5-AR 2 promoter region correlated with low expression of 5-AR 2 protein.
The transition zone of 42 human prostate tissues after radical prostatectomy was used for evaluation. Initially, 21 paraffin embedded samples were used to assess immunoreactivity to 5-AR 2 antibody in non-cancerous BPH samples. In the next 21 samples, fresh frozen prostate transition zone samples without cancer were assessed for immunoreactivity and methylation of the 5-AR 2 promoter using methyl-specific PCR.
We show that 6/21 (29%) of benign human prostate samples did not express the 5-AR 2 protein. Moreover, the promoter region of 5-AR 2 contains a CpG island that is methylated in benign prostate epithelial cells in culture and also in 39% (7/18) human prostate tissues. We show a strong correlation between methylation of the 5-AR 2 promoter region and absence of 5-AR 2 protein expression (P = 0.0025, Fisher's exact test).
Methylation of 5-AR 2 promoter may account for low or absent expression of 5-AR 2 in some human adult prostate tissues.
The Prostate 02/2011; 71(12):1317-24. · 3.48 Impact Factor
-
Aria F Olumi
The Journal of urology 06/2009; · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study is to investigate whether Fas-associated death domain interleukin-1 converting enzyme like inhibitory protein (FLIP) inhibition is a therapeutic target associated with 2-methoxyestradiol (2-ME2)-mediated tumor regression.
Expression and levels of FLIP were analyzed using (a) real-time PCR and immunoblot analysis in androgen-independent PC-3 cells treated with the newly formulated 2-ME2 and (b) immunohistochemistry in different Gleason pattern human prostate tumors. Transient transfections and chromatin immunoprecipitation (ChIP) assays were used to identify the transcription factors that regulate FLIP. Involvement of FLIP in 2-ME2-induced tumor regression was evaluated in transgenic adenocarcinoma mouse prostate (TRAMP) mice.
High Gleason pattern (5+5) human prostate tumors exhibit significant increase in FLIP compared with low Gleason pattern 3+3 (P=or<0.04). 2-ME2 reduced the levels and promoter activity of FLIP (P=0.001) in PC-3 cells. Transient expression assays show sequences between -503/+242 being sufficient for 2-ME2-induced inhibition of FLIP promoter activity. Cotransfection experiments show that overexpression of Sp1 activated, whereas Sp3 inhibited, Sp1 transactivation of FLIP promoter activity (P=0.0001). 2-ME2 treatment reduced binding of Sp1 to the FLIP promoter as evidenced by ChIP. Further, levels of FLIP associated with Fas or FADD decreased, whereas cleavage of caspase-8, levels of Bid, and apoptosis increased in response to 2-ME2 treatment in PC-3 cells. Administration of 2-ME2 regressed established prostate tumors in TRAMP mice that were associated with reduced expression of FLIP and Sp1.
Targeting Sp1-mediated FLIP signaling pathway may provide a novel approach for prostate cancer management.
Clinical Cancer Research 02/2009; 15(5):1601-11. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: TNFalpha and TRAIL, 2 members of the tumor necrosis factor family, share many common signaling pathways to induce apoptosis. Although many cancer cells are sensitive to these proapoptotic agents, some develop resistance. Recently, we have demonstrated that upregulation of c-Fos/AP-1 is necessary, but insufficient for cancer cells to undergo TRAIL-induced apoptosis. Here we present a prostate cancer model with differential sensitivity to TNFalpha and TRAIL. We show that inhibition of NF-kappaB or activation of AP-1 can only partially sensitize resistant prostate cancer cells to proapoptotic effects of TNFalpha or TRAIL. Inhibition of NF-kappaB by silencing TRAF2, by silencing RIP or by ectopic expression of IkappaB partially sensitized resistant prostate cancer. Similarly, activation of c-Fos/AP-1 only partially sensitized resistant cancer cells to proapoptotic effects of TNFalpha or TRAIL. However, concomitant repression of NF-kappaB and activation of c-Fos/AP-1 significantly enhanced the proapoptotic effects of TNFalpha and TRAIL in resistant prostate cancer cells. Therefore, multiple molecular pathways may need to be modified, to overcome cancers that are resistant to proapoptotic therapies.
International Journal of Cancer 12/2008; 124(8):1980-9. · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Using Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL) for cancer therapy is attractive, because TRAIL is effective against cancer cells without inducing significant cytotoxicity, making it an ideal cancer drug. However, some cancer cells evade TRAIL-induced apoptosis and become resistant. We have been investigating the molecular mechanisms that differentiate between TRAIL-resistant and TRAIL-sensitive prostate cancer cells. We have found that transcriptional regulation of the anti-apoptotic molecule, c-FLIP(L), can regulate sensitivity of cancer cells to TRAIL. We have found that c-Fos, represses expression of c-FLIP(L), and promotes TRAIL-induced apoptosis. Identifying molecular mechanisms that differentiate between sensitive and resistant cancer cells will help improve pro-apoptotic cancer therapies.
Methods in Enzymology 02/2008; 446:333-49. · 2.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previously, we have shown that c-Fos/activator protein-1 (AP-1) promotes tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by repressing the antiapoptotic molecule c-FLIP(L). In this study, we investigated whether synthetic induction of c-Fos/AP-1 by 12-O-tetradecanoylphorbol-13-acetate (TPA) converts the phenotype of TRAIL-resistant prostate cancer cells to a TRAIL-sensitive phenotype in vitro and in vivo.
Low-dose TPA was used to determine whether LNCaP prostate cancer cells could be converted to a TRAIL-sensitive phenotype in in vitro and in vivo studies. We also assessed whether TPA enhancement of TRAIL-induced apoptosis varies between androgen-sensitive and androgen-insensitive prostate cancer cells and evaluated the role of TRAIL receptors, DR4 and DR5, in TPA-enhanced TRAIL-induced apoptosis.
We show that the combination of TRAIL with low-dose TPA has no effect on nonmalignant prostate epithelial cells; however, TPA up-regulates most AP-1 proteins and AP-1 activity, reduces c-FLIP(L), and potentiates TRAIL-induced apoptosis. We show that the combination of TPA + TRAIL is effective in promoting apoptosis in both hormone-sensitive LNCaP and hormone-insensitive LNCaP-C4-2 prostate cancer cells. Although TPA enhances the TRAIL-receptor 1 (DR4) level, sensitization of prostate cancer cells seems to be more dependent on TRAIL-receptor 2 (DR5) than TRAIL-receptor 1 levels. In vivo xenograft experiments suggest that TPA elevates the expression of c-Fos and reduces c-FLIP(L). Combination of TPA with TRAIL-receptor 2 agonist antibody, lexatumumab, effectively increases apoptosis and reduces LNCaP xenograft tumor burden.
TPA, when combined with the proapoptotic agent TRAIL, is effective in changing the phenotype of some TRAIL-resistant prostate cancer cells to a TRAIL-sensitive phenotype.
Clinical Cancer Research 01/2008; 13(23):7181-90. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We reviewed and highlighted novel targeted apoptotic mediated therapies that can be used to treat prostate cancer.
A comprehensive review of the peer reviewed literature in the area of apoptosis was performed with special emphasis on apoptotic mediated pathways with promising novel targeted therapies that can be used for patients with prostate cancer.
The apoptotic pathway can be classified into 2 separate broad categories, including the extrinsic and the intrinsic pathways. Targeting the extrinsic or intrinsic mediated pathway holds promise for developing novel agents for treating prostate cancer. We discuss apoptosis related molecules and therapies, as categorized by 1) targeting apoptosis pathway for antitumor treatment, 2) targeting apoptosis regulators for antitumor treatment and 3) drugs that potentiate pro-apoptotic agents.
Defining the molecules responsible for apoptosis and their intricate molecular interactions will help guide us in developing drugs with less toxicity for appropriately selected patients with prostate cancer and other malignancies. Because neoadjuvant and adjuvant clinical trials are under way using novel pro-apoptotic agents for prostate cancer, it is imperative for urologists to be active members of the clinical research team and become familiar with the molecular pathways, and potential benefits and toxicities associated with these novel agents.
The Journal of Urology 12/2007; 178(5):1846-54. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies.
Cancer Research 11/2007; 67(19):9425-34. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Stromal-epithelial interactions play a critical role in development of benign prostatic hyperplasia. We have previously shown that stromal cells associated with prostatic carcinoma can potentiate proliferation and reduce cell death of prostatic epithelial cells. Genetic alterations in stromal cells affect stromal-epithelial interactions and modulate epithelial growth. The c-Jun proteins that are early transcription factor molecules have been shown to regulate stromal-epithelial interactions via paracrine signals. Moreover, the Jun-family member proteins have been shown to play an important role in proper development of the genitourinary organs. In this study, we show that c-Jun protein in fibroblasts regulates production and paracrine signals of insulin-like growth factor-1 (IGF-1). c-jun(+/+) fibroblasts secrete higher levels of IGF-1 and stimulate benign prostatic hyperplasia-1 cellular proliferation. In addition, stromally produced IGF-1 up-regulates epithelial mitogen-activated protein kinase, Akt, and cyclin D protein levels while down-regulating the cyclin-dependent kinase inhibitor p27. These data suggest that stromally expressed c-Jun may promote prostatic epithelial proliferation through IGF-1 as a paracrine signal that, in turn, can promote prostate epithelial proliferation. Identification of the signal transduction pathways between prostate epithelial cells and the surrounding stromal cells will improve our understanding of the normal and abnormal biology in prostatic diseases.
American Journal Of Pathology 11/2007; 171(4):1189-98. · 4.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The VHL tumor suppressor protein (pVHL) is part of an E3 ubiquitin ligase that targets HIF for destruction. pVHL-defective renal carcinoma cells exhibit increased NF-kappaB activity but the mechanism is unclear. NF-kappaB affects tumorigenesis and therapeutic resistance in some settings. We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. Elimination of these sites markedly enhanced Card9's ability to activate NF-kappaB in VHL(+/+) cells, and Card9 siRNA normalized NF-kappaB activity in VHL(-/-) cells and restored their sensitivity to cytokine-induced apoptosis. Furthermore, downregulation of Card9 in VHL(-/-) cancer cells reduced their tumorigenic potential. Therefore pVHL can serve as an adaptor for both a ubiquitin conjugating enzyme and a kinase. The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-kappaB activity and tumorigenesis.
Molecular Cell 11/2007; 28(1):15-27. · 14.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Clear cell carcinoma of the kidney is a major cause of mortality in patients with von Hippel-Lindau (VHL) disease, which is caused by germ line mutations that inactivate the VHL tumor suppressor gene. Biallelic VHL inactivation, due to mutations or hypermethylation, is also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for destruction under well-oxygenated conditions. All VHL mutations linked to classical VHL disease compromise this pVHL function although some missense mutations result in a low risk of kidney cancer (type 2A VHL disease) while others result in a high risk (type 2B VHL disease). We found that type 2A mutants were less defective than type 2B mutants when reintroduced into VHL-/- renal carcinoma cells with respect to HIF regulation. A stabilized version of HIF2alpha promoted tumor growth by VHL-/- cells engineered to produce type 2A mutants, while knock-down of HIF2alpha in cells producing type 2B mutants had the opposite effect. Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations.
Molecular and Cellular Biology 09/2007; 27(15):5381-92. · 5.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL-agonist compounds have the potential of being excellent cancer therapeutic agents with minimal cytotoxicity. Here, we examine the efficacy of the TRAIL-receptor 2 agonist, lexatumumab (Human Genome Sciences, Inc., Rockville, MD), and identify molecular pathways that differentiate between lexatumumab-sensitive and lexatumumab-resistance renal cancer cells. In an orthotopic metastatic mouse model, we first demonstrate that lexatumumab was effective in reducing the tumor burden of primary and metastatic lexatumumab-sensitive xenografts. We demonstrate that lexatumumab-sensitive cells were capable of triggering both the extrinsic and the intrinsic apoptotic pathways as demonstrated by caspase 8 and caspase 9 activations, respectively, after treatment with lexatumumab. In addition, expression of c-FLIP(L) protein, an important regulator of TRAIL-induced apoptosis, decreased, while expression of the TRAIL-receptor 2, DR5, increased. This study serves as a pre-clinical model for using TRAIL-like therapies for patients with advanced RCC.
Cancer Letters 07/2007; 251(1):146-57. · 4.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it induces apoptosis in cancer cells but not in normal cells. Unfortunately, some cancer cells develop resistance to TRAIL-induced apoptosis. Therefore, it is clinically relevant to determine the molecular mechanisms that differentiate between TRAIL-sensitive and TRAIL-resistant tumors. Previously, we have shown that the antiapoptotic molecule cellular-FLICE-inhibitory protein long isoform [c-FLIP(L)] is necessary and sufficient to maintain resistance to TRAIL-induced apoptosis. We have found that c-FLIP(L) is transcriptionally regulated by the activator protein-1 (AP-1) family member protein c-Fos. Here, we report that MG-132, a small-molecule inhibitor of the proteasome, sensitizes TRAIL-resistant prostate cancer cells by inducing c-Fos and repressing c-FLIP(L). c-Fos, which is activated by MG-132, negatively regulates c-FLIP(L) by direct binding to the putative promoter region of the c-FLIP(L) gene. In addition to activating c-Fos, MG-132 activates another AP-1 family member, c-Jun. We show that c-Fos heterodimerizes with c-Jun to repress transcription of c-FLIP(L). Therefore, MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating the AP-1 family members c-Fos and c-Jun, which, in turn, repress the antiapoptotic molecule c-FLIP(L).
Cancer Research 04/2007; 67(5):2247-55. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We determined the relationship between age adjusted free T, and stage, grade and the biochemical-free survival rate in patients with surgically treated prostate cancer.
A retrospective cohort study was done between 1995 and 2001 in 333 patients treated for clinically localized prostate cancer with radical retropubic prostatectomy by a single surgeon at our institution. The study cohort consisted of 279 patients (84%) who had free T levels available. Free T was assessed by single cutoff value of 1.5 ng/dl or less, as suggested by the assay manufacturer, or by age adjusted free T. The relationship of low free T as a single cutoff value and age adjusted reference ranges with clinical and pathological measures of disease progression were assessed using the Fisher exact and Wilcoxon rank sum tests with the outcome assessed by the log rank test.
Using the assay manufacturer suggested single cutoff value of 1.5 ng/dl or less to define low free T 57% of patients with prostate cancer in the cohort were categorized as hypogonadal. However, using age adjusted free T reference ranges only 2.5% of patients with prostate cancer were categorized as hypogonadal, which is more logical and representative of clinically significant hypogonadism in the general population. Poorly differentiated prostate cancer was associated with low free T when measured by a single cutoff value of 1.5 ng/dl or less, or by age adjusted free T (p = 0.017 and 0.04, respectively).
Low age adjusted free T as well as single cutoff free T correlates with poorly differentiated prostate cancer in surgically treated patients.
The Journal of Urology 05/2006; 175(4):1341-5; discussion 1345-6. · 3.75 Impact Factor
