Modulation of One-Carbon Metabolism by B Vitamins: Implications for Transformation and Progression of Prostate Cancer

Tisman, Glenn

doi:10.5772/25307

Cited by 2 publications

(4 citation statements)

References 211 publications

(205 reference statements)

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“…Deleterious DDR aberrations are associated with replication stress, placing increased demand for metabolic precursors such as folate and glutamate, which are crucial to DNA synthesis and repair. As such, given the enzymatic capability of PSMA to yield glutamate and folate monoglutamate from polyglutamated folates [2], and its reported role as a folate transporter [1], one possible explanation to account for this association is that PSMA overexpression in cells with deleterious DDR aberrations represents an adaptive cellular response. In this setting, PSMA overexpression may be being driven by the increased requirement of these cells for cellular metabolites such as folate and glutamate.…”

Section: Discussionmentioning

confidence: 99%

“…At the jejunal brush border, PSMA assists in folate absorption by removing the C-terminal glutamates from dietary folates. The role of PSMA in the prostate is less clear, although it has been implicated in folate and glutamate cellular uptake, which are key to DNA synthesis and repair, amino acid and polyamine generation, and PI3K-Akt signalling [1], [2], [3].…”

Section: Introductionmentioning

confidence: 99%

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Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

et al. 2019

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BackgroundProstate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility.ObjectiveTo elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR).Design, setting, and participantsMembranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data.Outcome measurements and statistical analysisExpression of mPSMA was quantitated by modified H-score. Patient DNA was tested by NGS. Gene expression and activity scores were determined from mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival was estimated by Kaplan-Meier test, and sample heterogeneity was quantified by Shannon's diversity index.Results and limitationsExpression of mPSMA at diagnosis was associated with higher Gleason grade (p = 0.04) and worse overall survival (p = 0.006). Overall, mPSMA expression levels increased at mCRPC (median H-score [interquartile range]: castration-sensitive prostate cancer [CSPC] 17.5 [0.0–60.0] vs mCRPC 55.0 [2.8–117.5]). Surprisingly, 42% (n = 16) of CSPC and 27% (n = 16) of mCRPC tissues sampled had no detectable mPSMA (H-score <10). Marked intratumour heterogeneity of mPSMA expression, with foci containing no detectable PSMA, was observed in all mPSMA expressing CSPC (100%) and 37 (84%) mCRPC biopsies. Heterogeneous intrapatient mPSMA expression between metastases was also observed, with the lowest expression in liver metastases. Tumours with DDR had higher mPSMA expression (p = 0.016; 87.5 [25.0–247.5] vs 20 [0.3–98.8]; difference in medians 60 [5.0–95.0]); validation cohort studies confirmed higher mPSMA expression in patients with deleterious aberrations in BRCA2 (p < 0.001; median H-score: 300 [165–300]; difference in medians 195.0 [100.0–270.0]) and ATM (p = 0.005; 212.5 [136.3–300]; difference in medians 140.0 [55.0–200]) than in molecularly unselected mCRPC biopsies (55.0 [2.75–117.5]). Validation studies using mCRPC transcriptomes corroborated these findings, also indicating that SOX2 high tumours have low PSMA expression.ConclusionsMembranous PSMA expression is upregulated in some but not all PCs, with mPSMA expression demonstrating marked inter- and intrapatient heterogeneity. DDR aberrations are associated with higher mPSMA expression and merit further evaluation as predictive biomarkers of response for PSMA-targeted therapies in larger, prospective cohorts.Patient summaryThrough analysis of prostate cancer samples, we report that the presence of prostate-specific membrane antigen (PSMA) is extremely variable both within one patient and between different patients. This may limit the usefulness of PSMA scans and PSMA-targeted therapies. We show for the first time that prostate cancers with defective DNA repair produce more PSMA and so may respond better to PSMA-targeting treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

et al. 2019

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“…Colombatti et al also suggested that treating LNCaP cells endogenously expressing PSMA with antibodies against PSMA induced proliferative MAPK pathway activation [ 50 ]. The abundance of PSMA in prostate tissue allows increased hydrolysis of the polyglutamated folates yielding glutamate and folate monoglutamate enabling the intake of folates into the cell via proton-coupled folate transporters (PCFT), reduced folate carriers (RFC), or possibly by PSMA itself [ 51 , 52 ]. Folate is crucial for one-carbon metabolism and is involved in the synthesis of DNA and RNA, and amino acid metabolism [ 51 ].…”

Section: The Role Of Psma In the Biology Of Prostate Cancermentioning

confidence: 99%

“…The abundance of PSMA in prostate tissue allows increased hydrolysis of the polyglutamated folates yielding glutamate and folate monoglutamate enabling the intake of folates into the cell via proton-coupled folate transporters (PCFT), reduced folate carriers (RFC), or possibly by PSMA itself [ 51 , 52 ]. Folate is crucial for one-carbon metabolism and is involved in the synthesis of DNA and RNA, and amino acid metabolism [ 51 ]. Some studies suggest that decreased folate levels cause epigenetic changes, DNA breaks, translocations, and uracil misincorporation into DNA suggesting a possible carcinogenic role for low folate levels [ 53 , 54 , 55 , 56 ] but the role of folate in cancer seems complex and also conflicting results exist, suggesting that decreased folate levels are a protective factor against prostate carcinogenesis [ 57 ].…”

Section: The Role Of Psma In the Biology Of Prostate Cancermentioning

confidence: 99%

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

Hyväkkä

Virtanen

Kemppainen

et al. 2021

Cancers

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Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer.

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Modulation of One-Carbon Metabolism by B Vitamins: Implications for Transformation and Progression of Prostate Cancer

Cited by 2 publications

References 211 publications

Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond

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