Biology subjects

Kittles, R. A.

Publications and source records attributed to Kittles, R. A..

4 recordsLinked to original sources

bioRxiv2025

Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men, with African American/Black (AA/B) men experiencing higher incidence and mortality than European American (EA) men. Obesity, which disproportionately affects AA/B men, is linked to increased PCa mortality, potentially through metabolic dysregulation. We hypothesize that methylglyoxal (MG), a reactive byproduct of glucose, lipid, and protein metabolism that is elevated in obesity, contributes to PCa progression. MG forms covalent adducts on DNA, RNA, and protein. We found that MG-adducts are elevated in AA/B men with PCa compared to EA men with PCa, as well as men without PCa. AA/B men with PCa had a higher frequency of SNP rs1049346 in glyoxalase 1 (GLO1), the primary MG detoxification enzyme. PCa cell lines from EA (C4-2) and AA/B (MDA-PCa-2b) men showed differential rs1049346 status, with C4-2 cells heterozygous and MDA-PCa-2b cells homozygous for the variant. This was associated with altered GLO1 expression and activity, with MDA-PCa-2b cells exhibiting reduced GLO1 function and increased MG-adducts compared to C4-2 cells. MG altered DNA repair and RNA processing pathways and induced distinct metabolic shifts in MDA-PCa-2b compared to C4-2 cells, including increased glycolysis and reduced oxidative phosphorylation. Transcriptomic analysis revealed unique MG-induced stress responses including a tenfold higher induction of TXNIP in MDA-PCa-2b vs. C4-2 cells, a gene inversely linked to GLO1 expression and activity. These findings suggest that MG stress may contribute to PCa progression in AA/B men through metabolic reprogramming and impaired detoxification, offering insight into potential precision medicine applications. Statement of SignificancePatients with obesity and diabetes have an elevated risk of cancer mortality. Defining how metabolic alterations contribute to this link is critical to understanding disease progression and identifying strategies to improve outcomes.

cancer biology↗

bioRxiv2022

Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

BackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined. ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients. ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.

cancer biology↗

bioRxiv2021

Racial differences in androgen metabolism and receptor signaling in prostate cancer

Dihydrotestosterone (DHT) and testosterone (T) mediated androgen receptor (AR) nuclear translocation initiates transcription of AR target genes that are pivotal for prostate cancer (PrCa) development and progression. Here we provide data indicating that in contrast to European American (EA) men, African American (AA) men with localized PrCa can exploit an alternative progesterone-androsterone-5-androstanedione pathway for DHT biosynthesis. Enzymes that are involved in alternate pathways of DHT biosynthesis are elevated in PrCa tissues from AA men, compared to EA men, and also correlated with increased serum DHT levels. In addition, higher serum DHT levels reflect increased RNA expression of AR target genes in PrCa tissues from AA men. Interestingly, serum T but not DHT levels are significantly lower in AA men compared to EA men with PrCa. Furthermore, serum progesterone and related intermediate metabolites levels that are produced during alternate pathways of DHT biosynthesis are significantly lower in AA men with PrCa and associated with a shorter time to disease progression. These data highlight that androgen biosynthesis is altered in therapy naive localized PrCa in AA men, and can potentially serve as prognostic indicators of disease progression. SignificanceOur work provides a rationale to examine potential pharmacological interventions that target androgen biosynthesis and AR signaling earlier in the disease continuum in AA men with PrCa. Additionally, our study lays the groundwork for developing serum measurements of intermediate androgen metabolites as PrCa prognostic biomarkers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/437727v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@932dd0org.highwire.dtl.DTLVardef@a4cca0org.highwire.dtl.DTLVardef@1764be4org.highwire.dtl.DTLVardef@1708a63_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Role of CYP3A5 in modulating androgen receptor signaling and its relevance to African American men with prostate cancer

BackgroundAndrogen receptor signaling is crucial for prostate cancer growth and is regulated by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high level of CYP3A5 protein, we tested the effect of blocking the wild type CYP3A5 in prostate cancer cells from AA men on androgen receptor signaling. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers (e.g. phenytoin and rifampicin) or inhibitors (e.g. ritonavir and amiodarone). In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling in prostate cancer cells. MethodsCell fractionation and immunofluorescence studies were performed to study AR nuclear localization and activation process using CYP3A5 siRNA and CYP3A5 inducers and inhibitors. A qPCR based array was employed to examine expression of AR downstream regulated genes after blocking CYP3A5 expression using a pool of CYP3A5 siRNA. Cell growth was monitored using MTS based assays. Since AAs tend to carry wild type CYP3A5 and non-Hispanic White Americans (NHWA) carry mutated CYP3A5 two cell lines one of AA origin (MDAPCA2b) carrying wt CYP3A5 and the other of NHWA origin (LNCaP) carrying mutant CYP3A5 were used for above experiments. ResultsSimilar to that observed in LNCaP (mutant CYP3A5) earlier, CYP3A5 siRNA treated MDACPA2b (AA, wild type CYP3A5) cells showed decreased AR nuclear translocation and PSA production. q-PCR based profiler assay identified several AR regulated genes which were downregulated with CYP3A5 siRNA pool treatment performed with cDNA from CYP3A5 siRNA pool and NT treated MDAPCA2b cells. These downregulated genes include SCL45A3, FKBP5, NCAPD3, MYC, MME, ELL2, PIK3R3, HPRT1 and SPDEF with p-value of [≤]0.005. These genes are known to regulate AR nuclear translocation, cell cycle progression and cell growth. SCL45A3, FKBP5, MYC, and ELL2 also showed decreased protein levels after CYP3A5 siRNA treatment. Commonly prescribed drugs which are either CYP3A5 inhibitors (amiodarone, ritonavir) or inducers (phenytoin, rifampicin) were tested for their ability to alter AR signaling in both LNCaP and MDAPCa2b cells. The results show that the CYP3A5 inducers promoted AR nuclear translocation and downstream signaling whereas CYP3A5 inhibitors abrogated them. The increased nuclear AR observed with phenytoin and rifampicin (CYP3A inducers) treatment is abrogated in CYP3A5 siRNA treated MDAPCa2b cells, confirming that the activation of AR activity is specific to changes in CYP3A5 activity. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. The difference in growth is more pronounced in MDAPCa2b cells which carries a wild type CYP3A5 as compared to LNCaP with the exception of ritonavir which also downregulates total AR levels. ConclusionsConcomitantly prescribed CYP3A5 modulating drugs may alter downstream AR signaling, cell growth and ADT efficacy in men, more so in AAs expressing wild type CYP3A5. Further, characterization and utilization of this observation how CYP3A5 inducers and inhibitors can alter AR signaling may provide guidance to physicians co-prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.

cancer biology↗