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Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells.

ABSTRACT: During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer (mCRPCa) to establish clinical relevance. The effect of glutamate deprivation or blockade by metabotropic glutamate receptor 1 (GRM1) antagonists was investigated on prostate cancer cells' growth, migration, and invasion to establish biologic relevance.Serum glutamate levels were measured in normal men (n = 60) and patients with primary prostate cancer (n = 197) or mCRPCa (n = 109). GRM1 expression in prostatic tissues was examined using immunohistochemistry (IHC). Cell growth, migration, and invasion were determined using cell cytotoxicity and modified Boyden chamber assays, respectively. Apoptosis was detected using immunoblotting against cleaved caspases, PARP, and ?-H2AX.Univariate and multivariate analyses showed significantly higher serum glutamate levels in Gleason score ? 8 than in the Gleason score ? 7 and in African Americans than in the Caucasian Americans. African Americans with mCRPCa had significantly higher serum glutamate levels than those with primary prostate cancer or benign prostate. However, in Caucasian Americans, serum glutamate levels were similar in normal research subjects and patients with mCRPC. IHC showed weak or no expression of GRM1 in luminal acinar epithelial cells of normal or hyperplastic glands but high expression in primary or metastatic prostate cancer tissues. Glutamate deprivation or blockade decreased prostate cancer cells' proliferation, migration, and invasion and led to apoptotic cell death.Glutamate expression is mechanistically associated with and may provide a biomarker of prostate cancer aggressiveness.

SUBMITTER: Koochekpour S

PROVIDER: S-EPMC3492499 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells.

Koochekpour Shahriar S Majumdar Sunipa S Azabdaftari Gissou G Attwood Kristopher K Scioneaux Ray R Subramani Dhatchayini D Manhardt Charles C Lorusso Giovanni D GD Willard Stacey S SS Thompson Hillary H Shourideh Mojgan M Rezaei Katayoon K Sartor Oliver O Mohler James L JL Vessella Robert L RL

Clinical cancer research : an official journal of the American Association for Cancer Research 20121016 21

<h4>Purpose</h4>During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer (mCRPCa) to establish clinical relevance. The effect of glutamate deprivation or blockade by metabotropic glutamate receptor 1 (GRM1) antagonists was investigated on prostate cancer cells' growth, migration, and invasion to establish biolo ...[more]

PMID: 23072969

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Project description:BackgroundG protein-coupled bile acid receptor 1 (GPBAR1) is a G protein-coupled receptor for bile acids, which is widely expressed in many human tissues. Patchouli alcohol (PA) has been shown to have an anti-cancer effect, including in prostate cancer (PCa). This study sought to confirm the regulatory mechanism of GPBAR1 in the anti-cancer activity of PA in PCa.MethodsThe SwissTargetPrediction website (Pro >0) was used to predict the target of PA. The UALCAN and The Cancer Genome Atlas-Prostate cohort was used to examine the differentially expressed genes and PCa recurrence. A gene set enrichment analysis (GSEA) was conducted to analyze the relationship between the expression of GPBAR1 and PCa proliferation, migration, and invasion. Cell proliferation, migration, and invasion were assessed by colony formation, 5-Ethynyl-2'-deoxyuridine staining, cell scratch assays, and Transwell invasion assays, respectively. A xenograft animal model was established to assess the effect of PA on tumor growth in vivo. GPBAR1 protein and apoptosis related protein expression was measured by western blot.ResultsGPBAR1 was a PA target predicted by the SwissTargetPrediction website. PA inhibited the expression of GPBAR1 in PCa cells in a time- and dose-dependent manner. The abnormal expression of GPBAR1 was related to cell proliferation, migration, and invasion. Additionally, GPBAR1 overexpression promoted the cell proliferation, migration, and invasion, and inhibited the apoptosis of PCa cells. GPBAR1 silencing inhibited the cell proliferation, migration, and invasion, and promoted the apoptosis of PCa cells. High expressions of GPBAR1 suppressed tumor growth in tumor-bearing mice. Further, GPBAR1 promoted the activation of nuclear factor kappa B (NF-κB) signaling, and PA regulated the malignant phenotypes of PCa cells via the NF-κB signaling pathway mediated by GPBAR1.ConclusionsGPBAR1 is a promising drug target of PA, and was shown to regulate the proliferation, apoptosis, migration, and invasion of PCa cells through GPBAR1/NF-κB inhibition.

Dataset Information

Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells.

Publications

Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells.

Similar Datasets

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