scholarly journals GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

2021 ◽  
Author(s):  
Anna Mukha ◽  
Ugur Kahya ◽  
Annett Linge ◽  
Oleg Chen ◽  
Steffen Lock ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Redox State ◽  
Cell Damage ◽  
Specific Antigen ◽  
Tumor Formation ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Blood Levels ◽  
Tumor Resistance ◽  
Prostate Cancer Stem Cells

Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

Prognostic value of free testosterone (FT) levels during salvage chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 152-152
Author(s):  
Christoph W. Reuter ◽  
Michael A. Morgan ◽  
Martin Fenner ◽  
Viktor Grünwald ◽  
Arnold Ganser
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Free Testosterone ◽  
Salvage Chemotherapy ◽  
Blood Levels ◽  
Weekly Docetaxel ◽  
Grade 3 ◽  
The Impact

152 Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Carboplatin, docetaxel and steroids interfere with testosterone biosynthesis and/or metabolism. In this study the impact of DC treatment on testosterone blood levels was analyzed. Methods: Docetaxel failure/resistance was defined as disease progression during docetaxel treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC patients (pts.) were treated with at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 plus docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) every 4 weeks and prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. FT levels were measured before (n=50) and during DC chemotherapy (n=43). Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 35/74 (47.3%) pts. At the current analysis the median follow-up time was 16.0 months and 54/74 pts. had died. Median progression-free survival (PFS) was 6.9 months (CI 95% 5.3, 8.4) and median overall survival (OS) was 18.6 months (CI 95% 12.4, 24.7). Median nadir FT levels were 2.8 pmol/L before and below the RIA detection limit of 0.6 pmol/L during DC treatment (p=0.011). While only 4/50 pts. had FT levels <0.6 pmol/L before DC treatment (all under abiraterone therapy), 27/43 pts. had nadir FT values <0.6 pmol/L during DC chemotherapy (p<0.001). FT levels <1 pmol/L during DC treatment were associated with a higher PSA response rate (hazard ratio HR 0.09; CI 0.02, 0.81, p=0.032) and FT levels <0.6 pmol/L with a higher OS (HR 0.45; CI 0.18, 0.98, p=0.045). FT remained statistically prognostic in multivariable analyses. The DC regimen was reasonably well tolerated, with leukopenia/ neutropenia as the most common reversible grade 3/4 toxicity (41.9/37.8%). Conclusions: These data demonstrate for the first time that FT is an important prognostic factor for PSAR and OS in mDRPC pts. receiving chemotherapy.

scholarly journals Apalutamide: a better option for the treatment of non-metastatic castration resistant prostatic carcinoma

2018 ◽  
Vol 7 (9) ◽  
pp. 1853 ◽  
Author(s):  
Raushan Kumar Ranjan ◽  
Akash Chandra
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Digital Rectal Examination ◽  
The Body ◽  
Blood Levels ◽  
Gnrh Analogue ◽  
Castration Resistant Prostate Cancer ◽  
Reductase Inhibitors ◽  
Castration Resistant ◽  
Cancer Of The Prostate

Prostate cancer is cancer of the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, some grow relatively quickly. The cancer cells may spread from the prostate to other area of the body, particularly the bones and lymph nodes. Factors that increase the risk of prostate cancer include older age, a family history of the disease, and race. About 99% of cases occur in males over the age of 50. Clinical features include hematuria, dysuria (painful urination),nocturia(urination at night). Lower blood levels of vitami D may increase the risk of developing prostate cancer. Infection with the sexually transmitted diseases, chlamydia, gonorrhea, syphilis and prostatitis seem to increase risk of prostate cancer. Diagnosis can be confirmed by digital rectal examination (DRE) with prostate-specific antigen (PSA) blood test, cystoscopy, transrectal ultrasonography and biopsy (The removal of small pieces of the prostate for microscopic examination). Medicines like 5-alpha-reductase inhibitors (finasteride and dutasteride) reduce the overall risk of prostate cancer. Apalutamide, sold under the brand name Erleada, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is taken by mouth. Apalutamide was first described in 2007 and was approved for the treatment of prostate cancer in February 2018. Apalutamide is used in conjunction with castration, either via bilateral orchiectomy or gonadotropin-releasing hormone analogue (GnRH analogue) therapy, as a method of androgen deprivation therapy in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).

scholarly journals Patient management tactics with primary detected prostate-specific antigen increase

2020 ◽  
Vol 9 (4) ◽  
pp. 41-46
Author(s):  
Marina S. Los
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Blood Levels ◽  
Gray Area ◽  
Puncture Biopsy ◽  
Anti Inflammatory ◽  
A Prospective Study

The main screening test for prostate cancer is the determination of prostate-specific antigen (PSA) in the blood. Increasing of the PSA level above 4 ng/ml is an indication for a detailed clinical examination of the patient. At the same time only in a quarter of cases with a PSA level of 4 to 10 ng/ml prostate cancer is diagnosed, and in 7080% of cases prostatic hyperplasia and prostatitis are diagnosed. Objective: to determine the need for anti-inflammatory treatment in the initial detection of elevated PSA blood levels within the gray area in men over 50 years of age to minimize the number of puncture biopsies of the prostate. Materials and methods. The study was divided into 2 parts. Part 1 a retrospective study, in which results of the histological examinations of the prostate gland of 297 men after a puncture biopsy about an increase in the PSA level of more than 4 ng/ml were analyzed. Part 2 a prospective study in which 118 men over 50 years of age with a primary increase in the PSA level from 4 to 9 ng/ml received anti-inflammatory treatment to monitor the dynamics of the PSA level. Results: the appointment of anti-inflammatory treatment allows in 69% cases to avoid puncture biopsy of the prostate, increase the predictive value of PSA, reduce the frequency of post-puncture complications of inflammatory genesis. Conclusion: the appointment of anti-inflammatory treatment is advisable when the primary increase in blood PSA levels to 9 ng/ml.

MP69-11 INFLUENCE OF BLOOD LEVELS OF PROSTATE-SPECIFIC ANTIGEN AT AGE 60 ON THE BENEFITS AND HARMS OF PROSTATE CANCER SCREENING

2014 ◽  
Vol 191 (4S) ◽  
Author(s):  
Sigrid Carlsson ◽  
Melissa Assel ◽  
Daniel Sjoberg ◽  
David Ulmert ◽  
Jonas Hugosson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Screening ◽  
Prostate Specific Antigen ◽  
Prostate Cancer Screening ◽  
Specific Antigen ◽  
Blood Levels

Prognostic value of free testosterone (FT) levels during salvage chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16024-e16024
Author(s):  
Christoph W. Reuter ◽  
Michael A. Morgan ◽  
Martin Fenner ◽  
Viktor Grünwald ◽  
Arnold Ganser
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Free Testosterone ◽  
Salvage Chemotherapy ◽  
Blood Levels ◽  
Weekly Docetaxel ◽  
Grade 3 ◽  
The Impact

e16024 Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Carboplatin, docetaxel and steroids interfere with testosterone biosynthesis and/or metabolism. In this study the impact of DC treatment on testosterone blood levels was analyzed. Methods: Docetaxel failure/resistance was defined as disease progression during docetaxel treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC patients (pts.) were treated with at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 plus docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) every 4 weeks and prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. FT levels were measured before (n=51) and during DC chemotherapy (n=41). Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 36/74 (48.6%) pts. At the current analysis the median follow-up time was 16.6 months and 56/74 pts. had died. Median progression-free survival (PFS) was 6.9 months (CI 95% 5.9, 7.9) and median overall survival (OS) was 18.6 months (CI 95% 12.4, 24.7). Median nadir FT levels were 2.8 pmol/L before and below the RIA detection limit of 0.6 pmol/L during DC treatment (p=0.008). While only 4/51 pts. had FT levels <0.6 pmol/L before DC treatment (all under abiraterone therapy), 28/41 pts. had nadir FT values <0.6 pmol/L during DC chemotherapy (p<0.0001). Median FT levels <0.9 pmol/L during DC treatment were associated with a higher PSA response rate (hazard ratio HR 0.19; CI 0.05, 0.78, p=0.021) and a higher OS (HR 0.34; CI 0.15, 0.81, p=0.015). FT remained statistically prognostic in multivariable analyses. The DC regimen was reasonably well tolerated, with leukopenia/ neutropenia as the most common reversible grade 3/4 toxicity (41.9/37.8%). Conclusions: These data demonstrate for the first time that FT is an important prognostic factor for PSAR and OS in mDRPC pts. during chemotherapy.

scholarly journals Influence of Intratumor Microbiome on Clinical Outcome and Immune Processes in Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2524
Author(s):  
Jiayan Ma ◽  
Aditi Gnanasekar ◽  
Abby Lee ◽  
Wei Tse Li ◽  
Martin Haas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Bradyrhizobium Japonicum ◽  
Large Scale ◽  
Specific Antigen ◽  
Sequencing Data ◽  
Tumor Node Metastasis ◽  
Prostate Cancer Stem Cells ◽  
Cancer Aggressiveness ◽  
Metastatic Growth

Although 1 in 9 American men will receive a diagnosis of prostate cancer (PC), most men with this diagnosis will not die from it, as most PCs are indolent. However, there is a subset of patients in which the once-indolent PC becomes metastatic and eventually, fatal. In this study, we analyzed microbial compositions of intratumor bacteria in PC to determine the influence of the microbiome on metastatic growth. Using large-scale RNA-sequencing data and corresponding clinical data, we correlated the abundance of microbes to immune pathways and PC risk factors, identifying specific microbes that either significantly deter or contribute to cancer aggressiveness. Interestingly, most of the microbes we found appeared to play anti-tumor roles in PC. Since these anti-tumor microbes were overrepresented in tumor samples, we believe that microbes thrive in the tumor microenvironment, outcompete cancer cells, and directly mitigate tumor growth by recruiting immune cells. These include Listeria monocytogenes, Methylobacterium radiotolerans JCM 2831, Xanthomonas albilineans GPE PC73, and Bradyrhizobium japonicum, which are negatively correlated with Gleason score, Tumor-Node-Metastasis (TNM) stage, prostate-specific antigen (PSA) level, and Androgen Receptor (AR) expression, respectively. We also identified microbes that contribute to tumor growth and are positively correlated with genomic alterations, dysregulated immune-associated (IA) genes, and prostate cancer stem cells (PCSC) genes.

scholarly journals MDA-9/Syntenin (SDCBP) Is a Critical Regulator of Chemoresistance, Survival and Stemness in Prostate Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 53 ◽  
Author(s):  
Sarmistha Talukdar ◽  
Swadesh K. Das ◽  
Anjan K. Pradhan ◽  
Luni Emdad ◽  
Jolene J. Windle ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Multiple Drug Resistance ◽  
Trichostatin A ◽  
Tumor Formation ◽  
Multiple Drug ◽  
Prostate Cancer Stem Cells

Despite some progress, treating advanced prostate cancer remains a major clinical challenge. Recent studies have shown that prostate cancer can originate from undifferentiated, rare, stem cell-like populations within the heterogeneous tumor mass, which play seminal roles in tumor formation, maintenance of tumor homeostasis and initiation of metastases. These cells possess enhanced propensity toward chemoresistance and may serve as a prognostic factor for prostate cancer recurrence. Despite extensive studies, selective targeted therapies against these stem cell-like populations are limited and more detailed experiments are required to develop novel targeted therapeutics. We now show that MDA-9/Syntenin/SDCBP (MDA-9) is a critical regulator of survival, stemness and chemoresistance in prostate cancer stem cells (PCSCs). MDA-9 regulates the expression of multiple stem-regulatory genes and loss of MDA-9 causes a complete collapse of the stem-regulatory network in PCSCs. Loss of MDA-9 also sensitizes PCSCs to multiple chemotherapeutics with different modes of action, such as docetaxel and trichostatin-A, suggesting that MDA-9 may regulate multiple drug resistance. Mechanistically, MDA-9-mediated multiple drug resistance, stemness and survival are regulated in PCSCs through activation of STAT3. Activated STAT3 regulates chemoresistance in PCSCs through protective autophagy as well as regulation of MDR1 on the surface of the PCSCs. We now demonstrate that MDA-9 is a critical regulator of PCSC survival and stemness via exploiting the inter-connected STAT3 and c-myc pathways.

scholarly journals Advances and Perspectives in Prostate Cancer Biomarker Discovery in the Last 5 Years through Tissue and Urine Metabolomics

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 181
Author(s):  
Ana Rita Lima ◽  
Joana Pinto ◽  
Filipa Amaro ◽  
Maria de Lourdes Bastos ◽  
Márcia Carvalho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Biomarker Discovery ◽  
Specific Antigen ◽  
Cancer Biomarker ◽  
Metabolic Reprogramming ◽  
The Past ◽  
Promising Strategy ◽  
Ideal Approach ◽  
Novel Biomarkers ◽  
The Impact

Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide. For its screening, serum prostate specific antigen (PSA) test has been largely performed over the past decade, despite its lack of accuracy and inability to distinguish indolent from aggressive disease. Metabolomics has been widely applied in cancer biomarker discovery due to the well-known metabolic reprogramming characteristic of cancer cells. Most of the metabolomic studies have reported alterations in urine of PCa patients due its noninvasive collection, but the analysis of prostate tissue metabolome is an ideal approach to disclose specific modifications in PCa development. This review aims to summarize and discuss the most recent findings from tissue and urine metabolomic studies applied to PCa biomarker discovery. Eighteen metabolites were found consistently altered in PCa tissue among different studies, including alanine, arginine, uracil, glutamate, fumarate, and citrate. Urine metabolomic studies also showed consistency in the dysregulation of 15 metabolites and, interestingly, alterations in the levels of valine, taurine, leucine and citrate were found in common between urine and tissue studies. These findings unveil that the impact of PCa development in human metabolome may offer a promising strategy to find novel biomarkers for PCa diagnosis.

scholarly journals The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4703
Author(s):  
Jakob Püschel ◽  
Anna Dubrovska ◽  
Ielizaveta Gorodetska
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Treatment ◽  
Treatment Strategies ◽  
Population Based ◽  
Tumor Resistance ◽  
Prostate Cancer Stem Cells ◽  
State Of Research

Cancer stem cells (CSCs) are the only tumor cells possessing self-renewal and differentiation properties, making them an engine of tumor progression and a source of tumor regrowth after treatment. Conventional therapies eliminate most non-CSCs, while CSCs often remain radiation and drug resistant, leading to tumor relapse and metastases. Thus, targeting CSCs might be a powerful tool to overcome tumor resistance and increase the efficiency of current cancer treatment strategies. The identification and isolation of the CSC population based on its high aldehyde dehydrogenase activity (ALDH) is widely accepted for prostate cancer (PCa) and many other solid tumors. In PCa, several ALDH genes contribute to the ALDH activity, which can be measured in the enzymatic assay by converting 4, 4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) aminoacetaldehyde (BAAA) into the fluorescent product BODIPY-aminoacetate (BAA). Although each ALDH isoform plays an individual role in PCa biology, their mutual functional interplay also contributes to PCa progression. Thus, ALDH proteins are markers and functional regulators of CSC properties, representing an attractive target for cancer treatment. In this review, we discuss the current state of research regarding the role of individual ALDH isoforms in PCa development and progression, their possible therapeutic targeting, and provide an outlook for the future advances in this field.

Relationship of alterations in the expression of nontargeted genes and suppression of bcl-2 by antisense oligonucleotides.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13513-e13513
Author(s):  
Marvin Rubenstein ◽  
Courtney M.P. Hollowell ◽  
Patrick Guinan
Keyword(s):  
Prostate Cancer ◽  
Gene Therapy ◽  
Growth Factor ◽  
Caspase 3 ◽  
Essential Gene ◽  
Cytotoxic T Cells ◽  
Specific Antigen ◽  
Creb Binding Protein ◽  
Tumor Resistance ◽  
Psma Expression

e13513 Background: Antisense oligos have been employed against prostate cancer models targeting proteins associated with growth/apoptosis. However gene therapy may not be totally specific. Oligos against bcl-2 are in clinical trials and it was of interest: 1) To see whether therapy produces non-specific effects compromising efficacy; 2) To identify genes whose activity may have to be maintained/replaced. Methods: In LNCaP cells we evaluated monospecific (directed against bcl-2) and bispecific (directed against bcl-2 & epidermal growth factor receptor) oligos which comparably suppressed bcl-2. Cells were evaluated by PCR for expression of non-targeted genes associated with apoptosis (caspase-3, clusterin); androgen regulation (androgen receptor [AR], p300, creb binding protein [CBP]); cytokines (interleukins 2 [IL-2], 4 [IL-4], interferon [IFN]); antigen expression (prostate specific antigen [PSA], prostate membrane antigen [PSMA], prostatic acid phosphatase [PAP]); and autocrine growth (insulin like growth factor [IGF1]). Results: Most non-targeted genes were unaffected. However following suppression of bcl-2 activity by mono- and bispecific oligos, cells compensated by suppressing caspase-3 (apoptosis promoter) and enhancing AR and coactivator p300 expression. This suggests an ability to reverse bcl-2 suppression of apoptosis through decreased expression of a promoter and increased androgen sensitivity. It identifies caspase-3 as an essential gene whose expression must be either maintained/replaced when bcl-2 is therapeutically suppressed. Among the differentiation antigens, cell surface PSMA expression was increased by bispecific oligos; secretory PSA and PAP were not. Increased PSMA may to be due to induced IFN expression produced by bispecific oligos, attributed to a 2X intrastrand conformation not seen in the monospecific oligo. Increased PSMA expression could make prostate cancer cells more recognizable to cytotoxic T cells and potentiate prostate cancer vaccines. Conclusions: If gene therapy is to be effective, the mechanisms for compensatory changes which contribute to tumor resistance must be further identified/controlled.

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