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

Effective therapeutic options have not existed for prostate cancer progressing after androgen deprivation therapy until very recently. Docetaxel based chemotherapy has been demonstrated to extend survival in 2 large randomized trials. These studies have provided the impetus to combine docetaxel with novel biologic agents to further consolidate the gains in long-term outcome. With the arrival of exciting agents including vaccines, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, antiangiogenic drugs, and small molecule receptor tyrosine kinase inhibitors, the future of prostate cancer therapy appears promising.
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PMID:New approaches in hormone refractory prostate cancer. 1660 42

Prostate cancer (PCA) is the most invasive malignancy and second leading cause of cancer deaths in American males. One approach to reduce PCA incidence, growth and metastasis is prevention and intervention targeted towards mitogenic and survival signaling and cell-cycle regulation. This approach is based on the rationale that overexpression of receptor tyrosine kinases (RTKs) and/or non-receptor tyrosine kinases leads to persistent autocrine stimulation of malignant cells for deregulated cell-cycle progression and uncontrolled growth. PCA progression has also been associated with transition from a paracrine to an autocrine relationship between receptors and growth ligands as this malignancy progresses to an advanced androgen-independent aggressive stage. Together, these studies suggest that targeting RTK-mediated signaling pathways along with cell-cycle regulators could be a practical and translational approach for PCA prevention and intervention. Here, we provide evidence that a naturally occurring nontoxic flavanoid, silibinin, targets the epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and NF-kappaB (nuclear factor-kappa B) pathways in PCA. Furthermore, it modulates cell-cycle regulators, including cyclin-dependent kinases (CDKs), Cip/Kip and cyclins for its anticancer efficacy against PCA. Silibinin inhibits growth of PCA cells from human, mouse, and rat origins, and also suppresses human prostate tumor xenograft growth in nude mice. Silibinin also inhibits PCA growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model. Now, silibinin has been entered into phase I/II clinical trials in human PCA patients where preliminary observations were suggestive of its further study in a larger base of the patient population.
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PMID:Prostate cancer chemoprevention by silibinin: bench to bedside. 1663 61

The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1alpha and HIF-1beta. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1alpha levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1alpha/HIF-1beta transcriptional activities. HIF-1alpha has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1alpha a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1alpha in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1alpha is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1alpha levels. In prostate cancer, androgens upregulate HIF-1alpha through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1alpha in endocrine oncology and present new data on HIF-1alpha signaling and the potential for targeted therapies, including combinatory hormonal therapies.
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PMID:Hypoxia-inducible factor-1 in human breast and prostate cancer. 1695 28

The functional consequences of changes in membrane lipid composition that coincide with malignant growth are poorly understood. Sufficient data have been acquired from studies of lipid binding proteins, post-translational modifications of signaling proteins, and biochemical inhibition of lipidogenic pathways to indicate that growth and survival pathways might be substantially re-directed by alterations in the lipid content of membranes. Cholesterol and glycosphingolipids segregate into membrane patches that exhibit a liquid-ordered state in comparison to membrane domains containing relatively lower amounts of these classes of lipids. These "lipid raft" structures, which may vary in size and stability in different cell types, both accumulate and exclude signaling proteins and have been implicated in signal transduction through a number of cancer-relevant pathways. In prostate cancer cells, signaling from epidermal growth factor receptor (EGFR) to the serine-threonine kinase Akt1, as well as from IL-6 to STAT3, have been demonstrated to be influenced by experimental interventions that target cholesterol homeostasis. The recent finding that classical steroid hormone receptors also reside in these microdomains, and thus may function within these structures in a signaling capacity independent of their role as nuclear factors, suggests a novel means of cross-talk between receptor tyrosine kinase-derived and steroidogenic signals. Potential points of intersection between components of the EGFR family of receptor tyrosine kinases and androgen receptor signaling pathways, which may be sensitive to disruptions in cholesterol metabolism, are discussed. Understanding the manner in which these pathways converge within cholesterol-rich membranes may present new avenues for therapeutic intervention in hormone-dependent cancers.
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PMID:Transit of hormonal and EGF receptor-dependent signals through cholesterol-rich membranes. 1717 42

Gonadotropin-releasing hormone (GnRH) analogs constitute the most widely employed medical treatment for prostatic cancer. The predominant mechanism of action is presumed to be via the inhibition of gonadotropins and resultant decrease in androgen. However, GnRH analogs have also been shown to directly inhibit prostate cancer cells both in vitro and in vivo through antiproliferative cell cycle arrest and stimulation of apoptosis. Since the GnRH receptor has been shown to affect sex steroid hormone receptor function, we considered that part of GnRH analog actions on prostate cells may be mediated through modulation of the human androgen receptor. Using a model HEK293 cell line expressing the GnRH receptor, we demonstrated a novel signalling pathway of the GnRH receptor that induces nuclear translocation of the androgen receptor that renders it transcriptionally inactive. This mechanism involves the calcium-dependent tyrosine kinase Pyk2, the non-receptor tyrosine kinase c-Src and the focal adhesion protein/steroid receptor co-factor, Hic-5. In this setting there is a GnRH-induced association and nuclear translocation of the androgen receptor with Hic-5. GnRH-induced Pyk2 activation opposed the association of Hic-5 with androgen receptor as overexpression of a dominant negative Pyk2 enhanced the GnRH-induced nuclear translocation of a green fluorescent protein-tagged human androgen receptor. GnRH-induced c-Src activation resulted in the phosphorylation of expressed Hic-5 and promoted its association with the human androgen receptor. In contrast to testosterone, GnRH-induced nuclear translocation did not transcriptionally activate the androgen receptor. We then demonstrated that GnRH can also stimulate androgen receptor mobilization in human prostate PC3, BPH-1 and LNCaP cells, and in cultured rat ventral prostate cells through the same mechanism. To determine if GnRH could antagonize androgen effects in normal tissue, we examined the effect of GnRH on rat ventral prostate organ cultures and demonstrated that GnRH can functionally antagonize the actions of testosterone on prostate cell proliferation and tissue growth. This antagonism of testosterone action by GnRH may underlie in part the capacity of GnRH receptor activation to inhibit prostate tumor growth.
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PMID:Gonadotropin-releasing hormone functionally antagonizes testosterone activation of the human androgen receptor in prostate cells through focal adhesion complexes involving Hic-5. 1720 4

Azurin is a member of a family of metalloproteins called cupredoxins. Although previously thought to be involved in electron transfer, azurin has recently been shown to preferentially enter cancer cells than normal cells and induce apoptosis in such cells. Azurin also demonstrates structural similarity to a ligand known as ephrinB2, which binds its cognate receptor tyrosine kinase EphB2 to initiate cell signaling. Eph/ephrin signaling is known to be involved in cancer progression. We now demonstrate that azurin binds to the EphB2-Fc receptor with high affinity. We have localized a C-terminal domain of azurin (Azu 96-113) that exhibits structural similarity to ephrinB2 at the G-H loop region known to be involved in receptor binding. A synthetic peptide (Azu 96-113) as well as a GST fusion derivative GST-Azu 88-113 interferes with the growth of various human cancer cells. In a prostate cancer cell line DU145 lacking functional EphB2, azurin or its GST-fusion derivatives had little cytotoxic effect. However, in DU145 cells expressing functional EphB2, azurin and GST-Azu 88-113 demonstrated significant cytotoxicity, whereas ephrinB2 promoted cell growth. Azurin inhibited the ephrinB2-mediated autophosphorlyation of the EphB2 tyrosine residue, thus interfering in upstream cell signaling and contributing to cancer cell growth inhibition.
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PMID:Cupredoxin-cancer interrelationship: azurin binding with EphB2, interference in EphB2 tyrosine phosphorylation, and inhibition of cancer growth. 1724 93

The insulin-like growth factor-1 receptor (IGF-1 receptor) is a receptor tyrosine kinase, highly homologous to the insulin receptor. In contrast to the insulin receptor, which is mostly involved in metabolic pathways, the IGF-1 system plays a pivotal role in normal and neoplastic cell growth through anti-apoptotic, proliferative and metastatic pathways. Furthermore, IGF-1 receptor over-activation is found to correlate with a variety of tumors, such as breast cancer, prostate cancer, hematological malignancies, colorectal cancer and other proliferative diseases, such as psoriasis and papilloma. In addition, accumulating evidence implies that blockade of IGF-1 receptor activity causes reversal of tumor progression in cell lines as well as in animal tumor models. Because of the central role the IGF-1 receptor plays in oncogenic maintenance and metastatic processes, it is a highly appropriate target for anti-cancer agents. Here we report on a novel substrate-mimic family of IGF-1 receptor inhibitors. These compounds are tertiary aromatic amines, non-competitive with ATP and possess high affinity towards the IGF-1 receptor. The most potent compound, SBL02 inhibited the IGF-1 receptor with an IC(50) of 170 nM in a cell-free kinase assay and was found to inhibit IGF-1 receptor auto-phosphorylation and substrate phosphorylation at the low micromolar range in cellular assays. SBL02 also blocks the formation of colonies in soft agar by cancer cells and inhibits the growth of keratinocytes and of HPV16 immortalized keratinocytes. This new family of non-ATP competitive, IGF-1 receptor inhibitors can serve as a lead for the development of anti-cancer, anti-psoriatic and anti-papilloma agents.
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PMID:ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic and anti-papilloma agents. 1737 30

The receptor tyrosine kinase ErbB-2 plays an important role in the regulation of growth factor-induced signal transduction cascades in the epithelium, and ErbB-2 is frequently overexpressed in epithelial tumors. Our previous studies on clinical prostate cancer specimens indicated that ErbB-2 expression was increased in patients undergoing hormone ablation therapy. We had also shown that the critical cell cycle regulatory gene cyclin D1 and its promoter were targets of proliferative signaling in prostate cancer cell lines, and that cyclin D1 was required for ErbB-2-induced mammary tumorigenesis. In the current studies, we found that increased ErbB-2 membrane expression correlated with increased nuclear cyclin D1 staining in clinical prostate cancer specimens, and that expression of ErbB-2 was capable of inducing cell cycle progression in human prostate cancer cell lines. We further showed that ErbB-2 induced the cyclin D1 promoter in DU145 cells, and that small interfering RNA knockdown of cyclin D1 protein levels blocked a significant proportion of the heregulin-induced cell cycle progression in LNCaP cells. Probasin promoter-targeted expression of an activated ErbB-2 isoform induced cyclin D1 expression in the mouse prostate, commensurate with prostate intraepithelial neoplasia. Together, these in vitro and in vivo studies identify cyclin D1 as a critical downstream target of ErbB-2 in the prostate epithelium, both of which are possible therapeutic targets for cancer intervention. Furthermore, our novel mouse model provides a useful platform for ongoing in vivo investigations of ErbB-2 signaling in the prostate epithelium.
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PMID:ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo. 1748 50

ErbB-3, an ErbB receptor tyrosine kinase, has been implicated in the pathogenesis of several malignancies, including prostate cancer. We found that ErbB-3 expression was up-regulated in prostate cancer cells within lymph node and bone metastases. Despite being a plasma membrane protein, ErbB-3 was also detected in the nuclei of the prostate cancer cells in the metastatic specimens. Because most metastatic specimens were from men who had undergone androgen ablation, we examined the primary tumors from patients who have undergone hormone deprivation therapy and found that a significant fraction of these specimens showed nuclear localization of ErbB3. We thus assessed the effect of androgens and the bone microenvironment on the nuclear translocation of ErbB-3 by using xenograft tumor models generated from bone-derived prostate cancer cell lines, MDA PCa 2b, and PC-3. In subcutaneous tumors, ErbB-3 was predominantly in the membrane/cytoplasm; however, it was present in the nuclei of the tumor cells in the femur. Castration of mice bearing subcutaneous MDA PCa 2b tumors induced a transient nuclear translocation of ErbB-3, with relocalization to the membrane/cytoplasm upon tumor recurrence. These findings suggest that the bone microenvironment and androgen status influence the subcellular localization of ErbB-3 in prostate cancer cells. We speculate that nuclear localization of ErbB-3 may aid prostate cancer cell survival during androgen ablation and progression of prostate cancer in bone.
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PMID:Bone microenvironment and androgen status modulate subcellular localization of ErbB3 in prostate cancer cells. 1763 23

Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. Effective treatments have not existed for prostate cancer progressing after androgen deprivation therapy until recently. Docetaxel based chemotherapy has demonstrated to extend patient survival in two large randomized studies. These studies have provided the impetus to combine docetaxel with novel biologic drugs to further consolidate the gains in long-term outcome. With the arrival of new therapies such as epothilone analogues, small molecule receptor tyrosine kinase inhibitors, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, antiangiogenics drugs and endothelin receptor antagonists, the future of prostate cancer therapy appears promising.
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PMID:[New targeted therapies in hormone-refractory prostate cancer]. 1784 95


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