Prostatic Neoplasms: Planet Earth

Muenchen HJ, Lin DL, Walsh MA, Keller ET, Pienta KJ. · Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0946, USA. · Clin Cancer Res. · Pubmed #10815922 links to  free full text

Abstract: Prostate cancer patients experiencing a relapse in disease often express high serum tumor necrosis factor-alpha (TNF-alpha) levels. Many androgen-insensitive prostate cancer cells are TNF-alpha insensitive because of the expression of antiapoptotic genes as part of the nuclear factor-kappaB (NF-kappaB) family of transcription factors. NF-kappaB stimulates gene transcription when expressed in the nucleus; however, in resting cells, this nuclear import is prevented by association with the cytoplasmic inhibitor IkappaBalpha. This cytoplasmic retention of NF-kappaB is uncoupled by many extracellular signals including low levels of TNF-alpha. During normal cell activation, nuclear translocation of NF-kappaB is preceded by phosphorylation and degradation of IkappaBalpha. When phosphorylation is blocked, IkappaBalpha remains intact, thereby blocking NF-kappaB translocation to the nucleus and subsequent activation of antiapoptotic genes that cause TNF-alpha insensitivity. We tested whether a "super-repressor" of NF-kappaB activity could be transfected into prostate cancer cells and make them TNF-alpha sensitive. PC-3 and LNCaP cells were stimulated with TNF-alpha (10 ng/ml) for 24 h in the presence or absence of the IkappaBalpha "super-repressor" (p6R-IkappaB(S32A + S36A)). NF-kappaB activity was measured by electrophoretic mobility shift assay and the steady state levels of the cytoplasmic IkappaBalpha protein were measured by Western blot. Secretory IL-6 and IL-6 mRNA were measured by ELISA. p6R-IkappaB(S32A + S36A) blocked the stimulation of NF-kappaB activity by TNF-alpha in prostate cancer cells. It also subsequently decreased IL-6 production by TNF-alpha. We conclude that these data demonstrate that inhibition of NF-kappaB selectively sensitizes previously insensitive prostate cancer cells to TNF-alpha.

Muenchen HJ, Poncza PJ, Pienta KJ. · Department of Internal Medicine (Division of Hematology/Oncology), University of Michigan, Ann Arbor, Michigan, USA. · Urology. · Pubmed #11182366 No free full text.

Abstract: OBJECTIVES: To investigate the molecular machinery of docetaxel (Taxotere)-initiated death signaling on prostate cancer cell lines LNCaP and PC-3. Taxotere is a member of the taxane family of chemotherapeutic agents. It has been shown to disrupt microtubule dynamics causing mitotic arrest, which leads to cell death. Taxotere has demonstrated induction of cell death in LNCaP and PC-3 cells. However, the pathways by which apoptosis occurs differ in each cell line. METHODS: The prostate cancer cell lines, LNCaP and PC-3, were treated with 40 nM Taxotere for various lengths of time (0.5 to 24 hours). Western blot analysis was used for protein analysis. RESULTS: LNCaP cells demonstrated caspase-3 and caspase-7 cleavage, and PC-3 cells demonstrated only caspase-8 and BH3-interacting domain death agonist cleavage. Only LNCaP cells were observed to express clusterin expression; PC-3 cells expressed a novel apoptosis inhibitor, survivin. CONCLUSIONS: In this study, we demonstrated two distinctly different Taxotere-induced apoptotic pathways in LNCaP and PC-3 cells that may be of clinical importance when treating prostate cancer.

Thakkar H, Chen X, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N, Srivastava RK. · Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Greenebaum Cancer Center, Baltimore, Maryland 21201-1180, USA. · J Biol Chem. · Pubmed #11461904 links to  free full text

Abstract: Tumor necrosis factor superfamily member TRAIL/Apo-2L has recently been shown to induce apoptosis in transformed and cancer cells. Some prostate cancer cells express constitutively active Akt/protein kinase B due to a complete loss of lipid phosphatase PTEN gene, a negative regulator of phosphatidylinositol 3-kinase pathway. Constitutively active Akt promotes cellular survival and resistance to chemotherapy and radiation. We have recently noticed that some human prostate cancer cells are resistant to TRAIL. We therefore examined the intracellular mechanisms of cellular resistance to TRAIL. The cell lines expressing the highest level of constitutively active Akt were more resistant to undergo apoptosis by TRAIL than those expressing the lowest level. Down-regulation of constitutively active Akt by phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002, reversed cellular resistance to TRAIL. Treatment of resistant cells with cycloheximide (a protein synthesis inhibitor) rendered cells sensitive to TRAIL. Transfecting dominant negative Akt decreased Akt activity and increased TRAIL-induced apoptosis in cells with high Akt activity. Conversely, transfecting constitutively active Akt into cells with low Akt activity increased Akt activity and attenuated TRAIL-induced apoptosis. Inhibition of TRAIL sensitivity occurs at the level of BID cleavage, as caspase-8 activity was not affected. Enforced expression of anti-apoptotic protein Bcl-2 or Bcl-X(L) inhibited TRAIL-induced mitochondrial dysfunction and apoptosis. We therefore identify Akt as a constitutively active kinase that promotes survival of prostate cancer cells and demonstrate that modulation of Akt activity, by pharmacological or genetic approaches, alters the cellular responsiveness to TRAIL. Thus, TRAIL in combination with agents that down-regulate Akt activity can be used to treat prostate cancer.

Xu K, Wang X, Ling M, Wong Y. · Department of Urology, People's Hospital, Peking University, Beijing 100044, China. · Chin Med J (Engl). · Pubmed #14642133 links to  free full text

Abstract: OBJECTIVE: To study the effects of an alpha(1)-adrenoceptor antagonist, terazosin on the androgen-independent prostate cancer cell lines PC-3 and DU145. METHODS: Two androgen independent cell lines, PC-3 and DU145, were used to determine cell viability, colony-forming ability, as well as cell cycle distribution, after exposure to terazosin. Western blot analysis was used to determine the expression of p21WAF1 and p27KIP1. RESULTS: This study shows that terazosin inhibits not only prostate cancer cell growth but also its colony forming ability, both of which are main targets of clinical treatment. In addition, terazosin is shown to inhibit cell growth through G1 phase cell cycle arrest and the up-regulation of p27(KIP1). CONCLUSION: This study provides evidence that the alpha(1)-adrenoceptor antagonist terazosin may have therapeutic potential in the treatment of advanced hormone refractory prostate cancer.

Dutta Roy S, Philip J, Javle P. · Research Unit, Department of Surgery, Leighton Hospital, South Cheshire, UK. · Int J Urol. · Pubmed #16045557 No free full text.

Abstract: OBJECTIVES: Prostate cancer is currently the commonest cancer in men of all ages in UK, but robust demographic data of its distribution in various socioeconomic classes is lacking. We aimed to analyze its incidence, mortality and survival trends in West Midlands, England, from 1986 to 2000 in terms of socioeconomic deprivation. METHODS: Data were collated from the regional cancer registry database and a well-validated demographic score, the Townsend band, was employed as an indicator of social deprivation, including four variables as proxy indicators of socioeconomic status. Individual cases were allocated to one of five deprivation categories using postcode at diagnosis. Regression trend analysis at 1 and 5 years was performed and a P-value derived from the t-test statistic. RESULTS: In the mid-1980s, the incidence rate ratio in affluent:deprived classes was 0.9, with age-standardized rates of 35.23 and 39.53 per 100 000 people. This ratio increased to 1.5 by 2000 with age-standardized rates of 95.98 and 63.13, respectively (172% increase in affluent compared with 60% in deprived). The affluent groups had a 7 and 13% survival advantage at 1 and 5 years; the survival advantage at 1 year was statistically significant (P=0.03). CONCLUSIONS: The preferential changes in incidence and survival in the affluent social classes are likely to be due to heightened awareness, resulting in increased prostate-specific antigen testing, which captures early and relatively slow-growing tumors with a better overall prognosis. If these bipolar trends are allowed to persist, then the gap between the affluent and deprived will continue to widen.

Abou-Elela A, Reyad I, Morsy A, Elgammal M, Bedair AS, Abdelkader M. · Urology Department, Cairo University, 1, Obour Buildings, Salah Salem Street, Nasr City, Cairo 35290, Egypt. · Eur J Surg Oncol. · Pubmed #17123772 No free full text.

Abstract: PURPOSE: Bladder neck preservation during radical prostatectomy has been advocated for improving urinary continence. We evaluate bladder neck preservation looking at continence rates, surgical cancer control and bladder neck contracture. MATERIALS AND METHODS: A total of 40 patients underwent retropubic radical prostatectomy for clinically localized carcinoma of the prostate. The prostatic urethra was dissected in continuity with the bladder away from the lumen of the prostate, which allows for a true urethra-to-urethra anastomosis. RESULTS: Continence was noted immediately in 26 patients, within 2 weeks in 9 and within 6 weeks in 3. Only 2 patients required pads 3 months postoperatively. Microscopic positive surgical margins were noted in 2 of 40 patients. In 1 patient the urethral margins were not involved with carcinoma. In the other patient the urethra was not the sole positive margin and microscopic positive margins were noted elsewhere. Early results of cancer control were good. CONCLUSIONS: Early follow-up of this technique of radical retropubic prostatectomy suggest that preservation of the continence mechanism at the level of the bladder neck and prostatic urethra results in significantly improved postoperative urinary continence without adversely affecting cancer control.

Guo J, Zhu T, Xiao ZX, Chen CY. · Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. · J Biol Chem. · Pubmed #17573344 links to  free full text

Abstract: An understanding of the molecular pathways defining the susceptibility of prostate cancer, especially refractory prostate cancer, to apoptosis is the key for developing a cure for this disease. We previously demonstrated that up-regulating Ras signaling, together with suppression of protein kinase C (PKC), induces apoptosis. Dysregulation of various intracellular signaling pathways, including those governed by Ras, is the important element in the development of prostate cancer. In this study, we tested whether it is possible to modulate the activities of these pathways and induce an apoptotic crash among them in prostate cancer cells. Our data showed that DU145 cells express a high amount of JNK1 that is phosphorylated after endogenous PKC is suppressed, which initiates caspase 8 cleavage and cytochrome c release, leading to apoptosis. PC3 and LNCaP cells contain an activated Akt. The inhibition of PKC further augments Akt activity, which in turn induces ROS production and the accumulation of unfolded proteins in the endoplasmic reticulum, resulting in cell death. However, the concurrent activation of JNK1 and Akt, under the condition of PKC abrogation, dramatically augment the magnitude of apoptosis in the cells. Thus, our study suggests that Akt, JNK1, and PKC act in concert to signal the intracellular apoptotic machinery for a full execution of apoptosis in prostate cancer cells.