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

It is well established that certain stress proteins or molecular chaperones are highly efficient in cross-presenting tumor-derived antigens, resulting in a potent antitumor immune response. In this study we demonstrate that genetic modification of weakly immunogenic murine prostate tumor cells (TRAMP-C2) by stable transfection with a secretable form of endoplasmic reticulum resident chaperone grp170 significantly enhances its immunogenicity in vivo. Generation of systemic antitumor immunity is indicated by the growth suppression of distant parental tumors, which is associated with increased tumor infiltration, elevated effector functions of CD8(+) T-cells. Immunization with inactivated grp170-secreting C2 cells augments a CD8(+) T-cell dependent, tumor-protective effect. Furthermore, infection of C2 tumor cells with a nonreplicating adenoviral vectors encoding secretable grp170 promotes tumor immunogenicity more effectively than plasmid transduction, as shown by the increased production of pro-inflammatory cytokine TNF-alpha by dendritice cells and enhanced therapeutic efficacy in treating pre-established tumors. Given a repertoire of undefined antigens in prostate tumor, manipulation of cellular compartmentalization of immuno-stimulatory chaperone grp170 to elicit systemic tumor immunity may be used to improve treatment outcomes for prostate cancer when combined with other treatment modalities.
 ...
PMID:Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor. 1914 36

Provirus integration site for Moloney murine leukemia virus (PIM1) is a proto-oncogene that encodes a serine/threonine kinase with multiple cellular functions. Overexpression of PIM-1 plays a critical role in progression of prostatic and hematopoietic malignancies. Here we describe the generation of a mAb specific for GST-PIM-1, which reacted strongly with most human and mouse cancer tissues and cell lines of prostate, breast, and colon origin but only weakly (if at all) with normal tissues. The mAb binds to PIM-1 in the cytosol and nucleus as well as to PIM-1 on the surface of human and murine cancer cells. Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice. These findings are important because they provide what we believe to be the first in vivo evidence that treatment of prostate cancer may be possible by targeting PIM-1 using an Ab-based therapy.
 ...
PMID:PIM-1-specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis. 1914 83

The present study shows that oral gavage of 6 mumol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were approximately 23% to 28% lower (P < 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression. The area occupied by the WD carcinoma was also approximately 44% lower in the DLP of SFN-treated mice relative to that of control mice (P = 0.0011 by Mann Whitney test). Strikingly, the SFN-treated mice exhibited approximately 50% and 63% decrease, respectively, in pulmonary metastasis incidence and multiplicity compared with control mice (P < 0.05 by t test). The DLP from SFN-treated mice showed decreased cellular proliferation and increased apoptosis when compared with that from control mice. Additionally, SFN administration enhanced cytotoxicity of cocultures of natural killer (NK) cells and dendritic cells (DC) against TRAMP-C1 target cells, which correlated with infiltration of T cells in the neoplastic lesions and increased levels of interleukin-12 production by the DC. In conclusion, the results of the present study indicate that SFN administration inhibits prostate cancer progression and pulmonary metastasis in TRAMP mice by reducing cell proliferation and augmenting NK cell lytic activity.
 ...
PMID:Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells. 1922 37

We recently synthesized a series of novel makaluvamine compounds, and found that the most potent was FBA-TPQ. The effects of FBA-TPQ on human (LNCaP and PC3) and murine (TRAMP C1) prostate cancer cells were evaluated. Potential mechanisms of action of the compound were also determined. FBA-TPQ exhibited dose-dependent cytotoxicity in the low micromolar range, inhibited proliferation, caused cell cycle arrest, and induced apoptosis in prostate cancer cell lines. The compound also decreased the expression of the androgen receptor and PSA. The results presented herein support the further development of FBA-TPQ as a novel agent for prostate cancer.
 ...
PMID:FBA-TPQ, a novel marine-derived compound as experimental therapy for prostate cancer. 1927 41

The androgen and androgen receptor (AR)-regulated gene expression plays important roles in normal prostate and prostate cancer development, and AR transcriptional control of genes is mediated by transcriptional coactivators, including the three members of the steroid receptor coactivator (SRC) family, SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2) and SRC-3 (AIB1, ACTR/RAC3/NCOA3). SRC-1 and SRC-3 are overexpressed in multiple human endocrine cancers and knockdown of either one of them in prostate cancer cell lines impedes cellular proliferation. Knockout of SRC-3 in mice suppresses the progression of spontaneous prostate carcinogenesis. In this study, we investigated SRC-1 contribution to prostate cancer in vivo by deleting the SRC-1 gene in TRAMP mice, which contain the probasin promoter-driven SV40 T/t antigen transgene. In assessing tumor mass of mice at various ages, we found that initiation and progression of prostate cancer induced by SV40 T/t antigens were unaltered in SRC-1(-/-) mice versus WT mice. Primary tumor histology and metastasis to distant lymph nodes were also similar in these mice at all time points assessed. These results demonstrate that the role of SRC-1 in mouse prostate carcinogenesis is nonessential and different from the essential contribution of SRC-3 that is required for prostate cancer progression and metastasis in mice. Interestingly, we observed that during prostate tumorigenesis SRC-1 expression was relatively constant, while SRC-3 expression was significantly elevated. Therefore, the loss of SRC-1 function may be compensated by SRC-3 overexpression during prostate tumorigenesis in SRC-1(-/-) mice.
 ...
PMID:The role of SRC-1 in murine prostate cancinogenesis is nonessential due to a possible compensation of SRC-3/AIB1 overexpression. 1930 43

Tumors express a wide variety of both mutated and nonmutated Ags. Whether these tumor Ags are broadly recognized as self or foreign by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA x TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-Ag (C3HA(high)), we examined the transcriptional profile of CD4 T cells undergoing Ag-specific division. Consistent with our previous data, transfer of Ag-specific CD4 T cells into C3HA(high) resulted in a functionally inactivated CD4 T cell profile. Conversely, adoptive transfer of an identical CD4 T cell population into ProHA x TRAMP mice resulted in the induction of a regulatory phenotype of the T cell (Treg) both at the transcriptional and functional level. Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development.
 ...
PMID:Tumor recognition and self-recognition induce distinct transcriptional profiles in antigen-specific CD4 T cells. 1934 43

The effect of thrombin on tumor cell cycle activation and spontaneous growth was examined in synchronized serum-starved tumor cell lines and a model of spontaneous prostate cancer development in TRAMP mice. BrdUrd incorporation and propidium iodide staining of prostate LNCaP cells arrested in G(0) and treated with thrombin or serum revealed a 48- and 29-fold increase in S phase cells, respectively, at 8 hours. Similar results were obtained with TRAMP cells and a glioblastoma cell line, T98G. Cell cycle kinases and inhibitors in synchronized tumor cells revealed high levels of p27(Kip1) and low levels of Skp2 and cyclins D1 and A. Addition of thrombin, TFLLRN, or serum down-regulated p27(Kip1) with concomitant induction of Skp2, Cyclin D1, and Cyclin A with similar kinetics. LNCaP p27(Kip1)-transfected cells or Skp2 knockdown cells were refractory to thrombin-induced cell cycle activation. MicroRNA 222, an inhibitor of p27(Kip1), was robustly up-regulated by thrombin. The in vitro observations were tested in vivo with transgenic TRAMP mice. Repetitive thrombin injection enhanced prostate tumor volume 6- to 8-fold (P < 0.04). Repetitive hirudin, a specific potent antithrombin, decreased tumor volume 13- to 24-fold (P < 0.04). Thus, thrombin stimulates tumor cell growth in vivo by down-regulation of p27(Kip1).
 ...
PMID:Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222. 1935 27

Considered a chemopreventive agent, the ability of genistein to modulate the progression of existing prostate cancer (CaP) is not clear. We show here that the consumption of genistein (250 mg/kg diet) by 12-week-old transgenic adenocarcinoma mouse prostate (TRAMP-FVB) mice harboring prostatic intraepithelial neoplasia lesions until 20 weeks of age induces an aggressive progression of CaP, as evidenced by a 16% increase in the number of well-differentiated and poorly differentiated prostates, coinciding with a 70% incidence of pelvic lymph node (LN) metastases as opposed to 0% and 10% in 0 and 1,000 mg/kg groups, concomitant with elevated osteopontin (OPN) expression in prostates and LNs. Equivalent nanomolar (500 nmol/L) concentrations of genistein recapitulated these effects in human PC3 CaP cells as evidenced by increased proliferation, invasion, and matrix metalloproteinase-9 (MMP-9) activity (approximately 2-fold), accompanied by an up-regulation of OPN expression and secretion, compared with vehicle-treated cells. A pharmacologic dose (50 micromol/L) decreased proliferation, invasion, and MMP-9 activity (>2.0-fold) concomitant with OPN reduction. Upon OPN knockdown by short hairpin RNA, genistein was no longer effective in up-regulating PC3 cell proliferation, invasion, and MMP-9 activation, which were significantly reduced in the absence of OPN, highlighting the requirement for OPN in mediating the effects of genistein. Proliferation, invasion, and OPN levels were also nonsignificantly induced by genistein in the presence of ICI 182,780 or wortmannin, indicating a dependence on phosphatidylinositol 3-kinase and estrogen signaling. Our results suggest the presence of a biphasic regulation of CaP growth and metastasis by genistein, warranting careful examination of the effects of genistein on hormone-dependent cancers in a chemotherapeutic setting.
 ...
PMID:Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. 1935 54

We found that relaxin peptide expression is significantly elevated in recurrent human prostate cancer. Stimulation with relaxin increased migration, invasiveness, proliferation, and adhesion of LNCaP and PC3 cells in vitro. Opposite effects on cellular phenotype were observed after suppression of endogenous relaxin/RXFP1 expression or signaling. We showed an accelerated progression of prostate cancer in TRAMP males with transgenic relaxin overexpression and a longer survival of TRAMP, RXFP1-deficient males. Suppression of RXFP1 expression in PC3 xenografts in nude mice by intratumoral injections of short interfering RNA resulted in decreased tumor size, cell proliferation, and metastasis rate.
 ...
PMID:Relaxin/RXFP1 signaling in prostate cancer progression. 1941 23

Retinoids, which include vitamin A (retinol) and metabolites such as retinoic acid, can inhibit tumor growth and reverse carcinogenesis in animal models of prostate cancer. We analyzed retinoid signaling and metabolism in the TRAMP (transgenic adenocarcinoma mouse prostate) model. We detected increased retinol and retinyl esters in prostates pooled from 24 to 36 week TRAMP transgenic positive mice compared to nontransgenic littermates by HPLC. We used quantitative RT-PCR to measure transcripts for genes involved in retinoid signaling and metabolism, including ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, LRAT, and RARbeta(2), in prostate tissue from TRAMP positive (+) and age-matched littermate control mice ranging from 18 to 36 weeks. Transcript levels of ALDH1A1, a putative stem cell marker, were decreased in ventral and lateral lobes of prostates from TRAMP mice compared to age-matched, nontransgenic mice. ALDH1A2 (RALDH2) mRNA levels in dorsal and anterior lobes of TRAMP+ mice were lower than in age-matched (24 week) nontransgenic mice. We detected lower RARbeta(2) mRNA levels in dorsal prostate lobes of 36 week TRAMP mice relative to nontransgenic mice. We detected high levels of ALDH1A2 protein in the cytoplasm and nucleus in nontransgenic murine prostate paraffin sections, and lower ALDH1A2 protein levels in all prostate lobes of TRAMP mice compared to nontransgenic mice by immunohistochemistry. We also detected much lower cytoplasmic ALDH1A2 protein levels in all human prostate cancer paraffin sections stained (19 total) relative to normal human prostate tissue on the same sections. Our data indicate that this reduction in ALDH1A2 protein is an early event in human prostate cancer.
 ...
PMID:Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model. 1954 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>