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Query: UNIPROT:P06889 (Mol)
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The crucial role played by androgens in the growth of prostatic carcinoma is now well established. However, the mechanisms of this proliferative action are still poorly understood. Experiments have been performed to clarify: (1) the metabolism of androgens in prostatic tumor cells; and (2) the role played by locally produced growth factors in the autocrine regulation of prostatic tumor cell proliferation and the possible regulation exerted by testosterone (T) on the activity of these factors. These studies have been performed by utilizing the human androgen-responsive prostatic cancer LNCaP cell line. (1) By incubating LNCaP cells with different 14C-labeled androgenic precursors, it has been shown that all the major key enzymes involved in the metabolism of androgens (5 alpha-reductase, 17 beta-hydroxysteroid-oxidoreductase, 3 alpha- and 3 beta-hydroxysteroid-oxidoreductases) are present and active in these cells. In particular, the 5 alpha-reductase, which converts T and delta 4 to DHT and 5 alpha-A respectively, seems to be more active when delta 4 is the substrate, suggesting a preference for this precursor. (2) The hypothesis that LNCaP cells might produce LHRH (or a LHRH-like peptide) has been verified by RT-PCR, performed in the presence of a pair of specific oligonucleotide primers. A cDNA band of the expected size (228 bp), which specifically hybridized with a 32P-labeled LHRH oligonucleotide probe, has been obtained in LNCaP cells. To clarify the possible role played by this factor in the regulation of tumor growth, LNCaP cells, cultured in steroid-free conditions, have been treated with a LHRH antagonist; the treatment resulted in a significant increase of cell proliferation. Taken together, these data indicate that a LHRH (or LHRH-like) growth modulatory system is expressed in LNCaP cells and plays an inhibitory role in the regulation of tumor cell proliferation. This system seems to be regulated in a negative way by steroids. Growth factors endowed with stimulatory activity, such as EGF and TGF alpha, have also been shown to be produced by LNCaP cells. The present studies show that the immunoprecipitation of the EGF receptor with a specific monoclonal antibody (Ab225) reveals a protein band of the expected size (170 kDa) which is phosphorylated even in basal conditions. Moreover, the treatment of LNCaP cells, cultured in serum-free conditions, either with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF and TGF alpha, results in a significant decrease of cell proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1995 Jun
PMID:Growth of the androgen-dependent tumor of the prostate: role of androgens and of locally expressed growth modulatory factors. 762 87

We investigated the ras p21 membrane localization and the expression and activation of protein kinase C (PKC) isozymes in activated ras oncogene-containing tumors and assessed whether these events were related to tumor growth. We used 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted SENCAR mouse skin tumors, which were shown to contain Ha-ras oncogene activated by point mutation at codon 61, as an in vivo model for these studies. Compared with levels in epidermis, highly elevated levels of membrane-bound Ha-ras p21 were observed in growing tumors, which also showed strong expression and membrane translocation of PKC zeta and beta II and weak expression of PCK alpha. However, when ras p21 membrane localization was blocked in vivo in growing tumors by lovastatin, opposite results were evident. Compared with saline-treated animals, in which tumor growth continued, lovastatin-treated animals had significantly inhibited tumor growth, which led to tumor regression with concomitant inhibition of Ha-ras p21 membrane localization. These regressing tumors from lovastatin-treated animals also showed a decrease in the expression and membrane translocation of PKC zeta and beta II but increased expression of PKC alpha. Taken together, our results indicate that ras p21 membrane localization and the expression and activation of PKC zeta, beta II, and alpha may be the critical events in the regulation of the growth of tumors that contain activated ras oncogenes.
Mol Carcinog 1995 Apr
PMID:Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen-induced murine skin tumors by lovastatin. 772 42

The effect of biological response modifiers on macroscopic tumor growth and on tumor cell proliferation of a human renal cell carcinoma and a squamous cell carcinoma (hypopharynx) in nude mice has been studied. Tumor necrosis factor alpha (TNF-alpha) and interferon alpha (IFN-alpha) as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) were applied either alone or in combination, and TNF-alpha was also combined with etoposide (ETP). TNF-alpha and IFN-alpha alone or in combination did not substantially affect the course of tumor growth, however, they did influence the pattern of tumor growth. There was also only a marginal effect on tumor cell proliferation. However, IFN-alpha protects the animals from tumor growth associated weight loss. ETP and ETP plus TNF-alpha leads to a deceleration of tumor growth, a decrease of the labeling index and to a significant decrease of the animal weight which indicates that the first two effects may be partly due to the toxicity of the treatment. GM-CSF modifies cell proliferation in a dose-dependent manner, i.e. stimulation at low doses and tendency to inhibition at higher doses. Although there is no substantial direct antineoplastic effect of the agents studied, the results make clear that indirect effects of therapeutic agents due to therapy induced cachexia should always be regarded. It is interesting that IFN-alpha has a protective effect against cachexia.
Cell Mol Biol (Noisy-le-grand) 1995 Feb
PMID:Effect of biological response modifiers on growth and cell proliferation of human tumor xenografts in nude mice. 777 38

Interleukin-1 (IL-1) is a growth arrest signal for diverse human tumor cell lines. We report here that the action of this cytokine in melanoma cells is associated with induction of EGR-1, a zinc finger protein that activates gene transcription. Both growth arrest and EGR-1 are induced via the type I receptor of IL-1. To determine the role of EGR-1 in IL-1 action in melanoma cells, we used a chimera expressing the transrepression domain of the Wilm's tumor gene, WT1, and the DNA binding domain of Egr-1. This chimera competitively inhibited EGR-1-dependent transactivation via the GC-rich DNA binding sequence, indicating that it acted as a functional dominant negative mutant of Egr-1. Melanoma cell lines stably transfected with the dominant negative mutant construct were supersensitive to IL-1 and showed accelerated G0/G1 growth arrest compared with the parental cell line. The effect of the dominant negative mutant construct was mimicked by addition of an antisense Egr-1 oligomer to the culture medium of the parental cells: the oligomer inhibited EGR-1 expression and accelerated the growth-inhibitory response to IL-1. These data imply that EGR-1 acts to delay IL-1-mediated tumor growth arrest.
Mol Cell Biol 1995 Feb
PMID:The zinc finger transcription factor EGR-1 impedes interleukin-1-inducible tumor growth arrest. 782 37

The concentrations of purine nucleotides, nucleosides and nucleobases in hepatocytes taken from healthy control mice and from Ehrlich ascites tumor bearing mice have been measured. The level of adenine nucleotides in the hepatocytes was higher during the proliferating phase in comparison with the resting phase of tumor growth and with control mice hepatocytes. The tracerkinetic studies on purine catabolism have been carried out on liver cells at different periods of tumor growth. The dynamics of radioactive tracers was mathematically modelled by a system of differential equations for both the concentrations and the specific radioactivities of the metabolites. Large differences in metabolic flux rates between control hepatocytes and hepatocytes in different phases of tumor growth were observed. The final purine degradation of hepatocytes was found to be accelerated in the resting phase but not in the proliferating phase of tumor growth. This result is in accordance with increased ATP concentration of liver itself in the proliferating phase of tumor growth. A conclusion is possible that the liver does not supply nucleosides and nucleobases for the Ehrlich ascites tumor cells during the proliferating phase of tumor growth.
Biochem Mol Biol Int 1994 Oct
PMID:Transitions of hepatic purine metabolism of Ehrlich ascites tumor bearing mice in different phases of tumor growth. 783 23

In previous studies, we observed that aromatase inhibitor 4-hydroxy-androstenedione (4-OHA) treatment significantly decreased estrogen (ER) and progesterone receptor (PR) concentrations in the uterus of ovariectomized (OVX) rats. To investigate whether similar effects occur in mammary tumors, we have studied the hormone-dependent, carcinogen (DMBA)-induced tumors of the rat. After 2 weeks of 4-OHA treatment both ER and PR were reduced in mammary tumors, as well as in uteri of intact animals (P < 0.05). Following ovariectomy, receptor levels were also reduced. A further reduction in receptor concentration in mammary tumors occurred with 4-OHA treatment in OVX animals (P < 0.001). Treatment of OVX rats with estradiol (0.2 microgram/ml) restored tumor PR concentrations to the level of the control, whereas ER levels were increased to concentrations slightly higher than the control. 4-OHA treatment partially inhibited this increase in ER in mammary tumors of OVX rats treated with estradiol. In contrast to ER concentrations, mRNA ER levels in the uterus were not decreased significantly by ovariectomy although mRNA levels were reduced in the tumors. Ovariectomy was without effect on mRNA PR in either tissue. Treatment with 4-OHA reduced mRNA levels of ER and PR in uterus and tumors in intact and OVX animals. Levels of tumor mRNA of both ER and PR were inhibited by 4-OHA treatment in estradiol treated OVX rats. Thus, 4-OHA appears to inhibit ER and PR concentrations in mammary tumors of the rat by reducing transcription. Although aromatase inhibition which results in decreased estrogen production, is the major antitumor effect of 4-OHA, reduction in ER and PR could contribute to effective estrogen blockade and limit tumor growth by antagonizing estrogen action as well as production.
J Steroid Biochem Mol Biol 1995 Jan
PMID:The effect of aromatase inhibitor 4-hydroxyandrostenedione on steroid receptors in hormone-dependent tissues of the rat. 785 75

By analysis of skin tumors from F1 hybrid mice we demonstrated that the genetic events that occur during tumor progression depend on the type of chemical carcinogenesis protocol used to induce tumor growth. More than 95% of tumors induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) exhibited mutations in Ha-ras and trisomy of chromosome 7. Carcinomas induced with multiple DMBA treatments had a lower frequency of alterations on chromosome 7 (50%), but only in tumors with Ha-ras mutations, and had a much wider spectrum of alterations, including trisomy, mitotic recombination, deletion, and gene duplication. Carcinomas induced with multiple N-methyl-N'-nitro-N-nitrosoguanidine treatments only rarely exhibited alterations on chromosome 7 (8%), even if they contained mutant Ha-ras. More frequent numerical alterations of chromosome 11 were also seen in TPA-promoted tumors (23%) than in tumors induced by multiple carcinogen treatments (8%). These results show that postinitiation events are nonrandom and fit a model in which promoting agents induce numerical chromosomal alterations but in which mutagens cause more directed mutational events.
Mol Carcinog 1994 Oct
PMID:Induction of different genetic changes by different classes of chemical carcinogens during progression of mouse skin tumors. 791 97

Mice with skin tumors induced either by 7,12-dimethylbenz[a]anthracene complete carcinogenesis or subcutaneous injection of a carcinogenic keratinocyte cell line showed moderate to severe splenomegaly as a result of an increase in splenic granulocyte-macrophage and erythroid (erythroid burst-forming unit) progenitors. To test whether the observed alterations involve the release of soluble factors by the epidermal component of skin tumors, we used an in vitro approach. A series of mouse keratinocyte cell lines resembling progressive stages of skin carcinogenesis and carrying either normal or activated Ha-ras genes were assayed for their ability to produce the factors required for colony growth of hematopoietic-committed progenitors. Only the conditioned media of keratinocytes harboring activated Ha-ras genes were able to support the growth of granulocyte-macrophage colony-forming units. In addition, preincubation of normal bone-marrow cells with conditioned media from the transformed epidermal cell lines stimulated in vitro amplification of the hematopoietic granulocyte-macrophage progenitor compartment. To identify the possible factors responsible for the activities detected in the keratinocyte-conditioned media, we performed northern blot analysis using the cytokine probes granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, stem cell factor, interleukin-1 alpha, interleukin-3, and tumor necrosis factor-alpha. The cell lines expressed different cytokine mRNA combinations that positively correlated with the colony-stimulating activity detected in the corresponding conditioned medium. These results suggest that transformed epidermal tumor cells in vivo may alter normal hematopoiesis as a consequence of the production of cytokines that act in autocrine or paracrine loops probably related to tumor growth.
Mol Carcinog 1994 Nov
PMID:Augmented expression of cytokines in mouse epidermal tumor cells and its possible involvement in the induction of hematopoietic alterations. 794 4

Sex steroids, in particular estradiol (E2) and progesterone (P4), play, together with other hormones and growth factors, a role in the development of normal breast tissue. The effect of four progestagens (norethisterone, 3-ketodesogestrel, gestodene and P4) and Org OD14, a steroid with weak estrogenic, progestagenic and androgenic properties were studied on growth of breast tumor cells in vitro using two subclones of MCF-7 (H and A) and T47D (S and A) cells. In addition, we investigated the effects of 3-ketodesogestrel, gestodene and Org OD14 on the growth of 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors in rats. In the in vitro assays with MCF-7 cells norethisterone, 3-ketodesogestrel and gestodene stimulated growth only at high doses (> or = 10(-7) M), whereas P4 had no effect. Gestodene was more potent than 3-ketodesogestrel and norethisterone. Org OD14, stimulated cell growth at a dose of 10(-8) M, while E2 is active at 10(-10) M. In T47D-A cells similar effects were found, but the subclone S did not respond to the progestagens and Org OD14. The two T47D subclones also reacted differently to progestagens during growth stimulation with E2. In T47D-S the progestagens and Org OD14 inhibited, while in T47D-A these compounds did not modulate the effect of E2. In the DMBA model we found that gestodene and 3-ketodesogestrel were able to inhibit tumor growth to the same extent. Surprisingly, Org OD14 was even more effective in the DMBA model using the therapeutic approach. Using the prophylaxic approach tumor development was delayed and tumor growth was strongly suppressed. The inhibitory effects of Org OD14 on tumor growth in the DMBA model may be attributed to its mixed hormonal profile. From these studies we conclude that different cell lines and even subclones thereof respond quite differently to steroids. Both in vitro and in vivo studies are required to judge whether synthetic steroids might be involved in an increased risk for the development of breast tumors.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Effects of progestagens and Org OD14 in in vitro and in vivo tumor models. 804 94

Recent studies have established that concentration gradients of aromatase expression occur within the breast, with the highest levels of expression occurring in sites proximal to a tumor. These variations in aromatase expression correlate with regional differences in the relative proportions of the histologic components of breast adipose tissue, in particular adipocytes and stromal cells, since regions containing the highest numbers of stromal cells are the sites of elevated aromatase transcript levels. Although the initiating events are unknown, it is proposed that, once neoplastic cells start to replicate, tumor growth will be promoted by locally increased estrogen levels. In turn, growth factors produced by the tumor in response to locally increased estrogen levels may further increase aromatase expression in the surrounding adipose tissue. Thus a positive feed-back loop is established in which locally-produced estrogens and tumor-derived growth factors act by paracrine and autocrine mechanisms to sustain the growth and development of the tumor. Further support for this concept is obtained from the observation that aromatase expression in breast adipose is regulated by enhancer elements that appear to respond positively to growth factors, in contrast to expression in granulosa cells, which is inhibited by growth factors.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Aromatase gene expression in adipose tissue: relationship to breast cancer. 804 95


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