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)

The aim of our study was to determine whether leptin, a hormone implicated in both energy-balance and reproductive function, is involved in the etiology of prostate cancer or benign prostatic hyperplasia (BPH). We compared the serum leptin levels of 43 cases of incident prostate cancer, 41 patients with BPH, and 48 healthy controls, all recruited in Athens, Greece. Multiple logistic regression modeling was used, with adjustment for age, height, body mass index, education, estradiol, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin and insulin like growth factor 1. Odds ratios per 4 ng/ml increment of leptin were 0.70 [95% confidence interval (CI) (0.32,1.55)] for prostate cancer and 1.06 [95% CI (0.67,1.67)] for BPH. After adjustment for body mass index, serum leptin levels were not significantly correlated with levels of any of the other hormones under study. Leptin levels are unlikely to affect the risk of either prostate cancer or BPH substantially.
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PMID:Leptin in relation to prostate cancer and benign prostatic hyperplasia. 953 57

A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1-3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk.
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PMID:Leptin is associated with increased prostate cancer risk: a nested case-referent study. 1123 30

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgen-independent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.
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PMID:Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. 1290 51

Leptin's relation with obesity has been clearly demonstrated while its role in oncobiology is still largely unknown. Epidemiological studies on serum leptin provide valuable though controversial data, while in vitro studies consistently show leptin's angiogenic and proliferative potential in cancer. Leptin's activity is mediated by tissue-specific receptors, differentially expressed in organs such as the prostate. The molecular cascades triggered by leptin result in prostatic cell proliferation and angiogenic activity, thus linking the hormone mainly to prostate cancer prognosis. This review also addresses leptin's metabolic interactions with cytokines, growth factors or hormones, establishing perceptive pathways leading to carcinogenesis or prostate cancer progression and metastasis. Better understanding of these mechanisms may help in the development of new and more effective treatments for prostate cancer. The consolidation of leptin molecular genetics profile in prostate cancer patients may help to create susceptibility groups in normal individuals, facilitating a preventive dietary intervention or strategies for chemoprevention. We hypothesize that the balance between androgen and leptin levels may facilitate the increase in the ratio of androgen-independent prostate cancer cells to androgen-dependent cells in the tumour.
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PMID:Leptin and prostate: implications for cancer prevention--overview of genetics and molecular interactions. 1545 47

In an era of rapidly increasing prevalence of human obesity and associated health problems, leptin gene polymorphisms have drawn much attention in biomedical research. Leptin gene polymorphisms have furthermore drawn much attention from animal scientists for their possible roles in economically important production and reproduction traits. Of the polymorphisms reported for exonic, intronic, and promoter regions of the leptin gene, 16 have been included in association studies in humans, 19 in cattle, and 6 (all exonic or intronic) in pigs. In humans, associations have been found with overweight or (early-onset) obesity, non-insulin-dependent diabetes mellitus, prostate cancer, and non-Hodgkin's lymphoma. In cattle, associations have been found with feed intake, milk yield traits, carcass traits, and reproduction-related traits, and in pigs with feed intake, average daily gain, carcass traits (backfat/leanness), and reproduction performance traits. Many of the polymorphisms were only included in a limited number of association studies, or the phenotypes studied varied largely for a given polymorphism between studies. Therefore, many of the associations found for these polymorphisms need to be confirmed in future studies before firm conclusions can be drawn.
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PMID:Leptin gene polymorphisms and their phenotypic associations. 1611 75

Obesity-associated prostate cancer (PCa) remains controversial, although most studies rely on body mass index evaluation, which is an indirect measure of fatness. Studies using body fat measurement and disease stratification according to PCa stage found stronger associations between obesity and PCa. Leptin is a pleiotrophic hormone mainly synthesized by adipocytes that acts in peripheral organs such as the prostate. This article reviews obesity-associated leptin's pathophysiological role in PCa progression. PCa development results from some known risk factors. Currently, there is enough evidence suggesting that leptin is an additional factor involved in advanced PCa occurrence, and obesity association with high-grade disease. Life-long exposure to genetic and/or environmental susceptibility factors that predispose to obesity and higher leptin levels may increase the risk for advanced PCa.
Prostate Cancer Prostatic Dis 2006
PMID:The link between obesity and prostate cancer: the leptin pathway and therapeutic perspectives. 1679 46

Circulating insulin-like growth factor binding protein 1 (IGFBP-1), leptin, and insulin are 3 proteins modified by obesity and have been associated with cancer at several sites in past studies. We conducted a cross-sectional study to describe the correlation of these proteins with gender, race/ethnicity, anthropometric indexes, and dietary and lifestyle factors. We measured fasting plasma levels of IGFBP-1, leptin, and C-peptide, used here as a stable measure of insulin secretion, in a random sample of 450 male and 352 postmenopausal female Hawaii and Los Angeles Multiethnic Cohort Study (MEC) participants (age range 47-82 yr at blood draw). Through a series of multiple linear regressions, we found that the most parsimonious model for plasma IGFBP-1 included inverse associations with age, body mass index (BMI), and regular soda intake. A term for interaction between age and BMI was positively associated with plasma IGFBP-1. Adjusted mean plasma leptins were highest among Whites and African Americans and lowest among Hawaiians and Japanese Leptin was also inversely associated with age and positively associated with the interaction between age and race/ethnicity, female gender, and BMI. A model with only race/ethnicity and BMI (positive association) was best for plasma C-peptide. Adjusted means for C-peptide were highest for Japanese and Whites and lowest for African Americans. The overall percent of variance in protein levels explained by these models was low for IGFBP-1(R2=0.17) and C-peptide (R(3)=0.11) and higher for leptin (R(2)=0.57). We saw no clear correlation between racial/ethnic trends in protein levels with those of colorectal, breast, or prostate cancer incidence rates in the MEC. Research to clarify factors associated with determination of these proteins and their relationship with cancer etiology is warranted.
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PMID:Lifestyle and dietary correlates of plasma insulin-like growth factor binding protein-1 (IGFBP-1), leptin, and C-peptide: the Multiethnic Cohort. 1764 Jan 59

Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP) cells as well as androgen-insensitive (PC-3 and DU-145) cells. At a concentration of 200 nm, LNCaP cells showed a significant increase (20% above control; P < .0001) in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P < .01 to P < .0001) dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity.
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PMID:Differential effects of leptin on the invasive potential of androgen-dependent and -independent prostate carcinoma cells. 1858 49

Obesity is associated with advanced prostate cancer. Here we demonstrate that in mouse prostate cancer TRAMP-C1 cells epididymal fat extracts from high-fat diet-fed obese mice stimulate androgen-independent cell growth more significantly than those from low-fat diet-fed lean mice or genetically obese leptin-deficient ob/ob mice in correlation with leptin concentrations. This result suggests that obesity promotes androgen-independent prostate cancer cell growth via adipose leptin. We have reported that added leptin stimulates androgen-independent prostate cancer cell proliferation through c-Jun NH(2)-terminal kinase (JNK). As with JNK, signal transducer and activator of transcription 3 (STAT3) and Akt are implicated in androgen-independent prostate cancer. In this study, we identify novel interaction of these three molecules in leptin-stimulated androgen-independent cell proliferation. Leptin activates JNK, STAT3 and Akt in a biphasic manner with a similar time-course. Pharmacological JNK inhibition suppresses leptin-stimulated DNA binding activity, as well as Ser-727 phosphorylation, of STAT3. Since JNK upregulates STAT3 activity via Ser-727 phosphorylation, JNK mediates leptin-stimulated STAT3 activation through Ser-727 phosphorylation. Moreover, JNK inhibition impairs leptin-stimulated Ser-473 phosphorylation of Akt that is required for its activation. Thus, JNK is involved in leptin-stimulated Akt activation. These findings together indicate that JNK mediates leptin-stimulated androgen-independent prostate cancer cell proliferation via STAT3 and Akt.
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PMID:c-Jun NH(2)-terminal kinase mediates leptin-stimulated androgen-independent prostate cancer cell proliferation via signal transducer and activator of transcription 3 and Akt. 1871 31

Hyperinsulinemia and obesity-related metabolic disturbances are common and have been associated with increased cancer risk and poor prognosis. To investigate this issue in relation to prostate cancer, we conducted a nested case-control study within the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial testing finasteride versus placebo for primary prevention of prostate cancer. Cases (n = 1,803) and controls (n = 1,797) were matched on age, PCPT treatment arm, and family history of prostate cancer; controls included all eligible non-whites. Baseline bloods were assayed for serum C-peptide (marker of insulin secretion) and leptin (an adipokine) using ELISA. All outcomes were biopsy determined. Logistic regression calculated odds ratios (OR) for total prostate cancer and polytomous logistic regression calculated ORs for low-grade (Gleason <7) and high-grade (Gleason >7) disease. Results were stratified by PCPT treatment arm for C-peptide. For men on placebo, higher versus lower serum C-peptide was associated with a nearly 2-fold increased risk of high-grade prostate cancer (Gleason >7; multivariate-adjusted OR, 1.88; 95% confidence interval, 1.19-2.97; P(trend) = 0.004). When C-peptide was modeled as a continuous variable, every unit increase in log(C-peptide) resulted in a 39% increased risk of high-grade disease (P = 0.01). In contrast, there was no significant relationship between C-peptide and high-grade prostate cancer among men receiving finasteride. Leptin was not independently associated with high-grade prostate cancer. In conclusion, these results support findings from other observational studies that high serum C-peptide and insulin resistance, but not leptin, are associated with increased risk of high-grade prostate cancer. Our novel finding is that the C-peptide-associated risk was attenuated by use of finasteride.
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PMID:Finasteride modifies the relation between serum C-peptide and prostate cancer risk: results from the Prostate Cancer Prevention Trial. 2017 95


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