A5093116033- Pharmacological Receptor Mechanisms and Effects
- PARP inhibition in cancer therapy
- Protein Degradation and Inhibitors
- Tryptophan and brain disorders
- Endoplasmic Reticulum Stress and Disease
- Peptidase Inhibition and Analysis
- Advanced Proteomics Techniques and Applications
- Autophagy in Disease and Therapy
- Computational Drug Discovery Methods
- Adipose Tissue and Metabolism
- Mitochondrial Function and Pathology
- Cancer, Stress, Anesthesia, and Immune Response
- Extracellular vesicles in disease
- Nanoplatforms for cancer theranostics
Thomas Jefferson University
2023-2025
Sidney Kimmel Cancer Center
2023-2025
Sidney Kimmel Comprehensive Cancer Center
2025
Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was first defined and validated adaptive mechanism. The endoplasmic reticulum (ER) is central as modulatory secreted integral membrane proteins are dependent on ER. Sigma1 a unique ligand-regulated scaffolding protein enriched ER cells. PD-L1 an glycoprotein that translated into processed through cellular secretory...
Lipid droplets (LD) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer, LD accumulation is associated with cancer aggressiveness, therapy resistance, poor clinical outcome. Prostate arises an androgen receptor (AR)-driven disease. Among its myriad roles, AR mediates the biosynthesis LDs, induces...
<div>Abstract<p>Lipid droplets (LD) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer, LD accumulation is associated with cancer aggressiveness, therapy resistance, poor clinical outcome. Prostate arises an androgen receptor (AR)-driven disease. Among its myriad roles, AR mediates...
<p>Pharmacologic Sigma1 inhibitor eliminates DHT-induced AR-mediated LDs by lipophagy. Treatment with a small-molecule AR and ARV7 mediated LDs. Confocal image of HCS LipidTox stained (red) in LNCaP cells (<b>A</b>), C4-2 (<b>B</b>), VCaP (<b>C</b>) treated drug vehicle (DMSO), DHT (1 nmol/L, 3 days), treatment days) combined (IPAG, 10 µmol/L, added for the final 16 hours 3-day treatment), DAPI nuclei (blue). Quantification expressed as mean number...
<p>Sigma1 KD suppresses DHT induced prostate cancer cell proliferation and tumor growth despite (or due to) increased autophagy. <b>A,</b><i>In vitro</i> assay of Sigma1 shRNA-transduced LNCaP C4-2 cells precultured in CSS medium for 3 days then treated 6 with 1 nmol/L DHT. Live were counted by Trypan blue exclusion at the start time course (day 0), treatment. Data are represented as fold induction over control shRNA day 0. Datapoints represent mean increase...
<p>GSEA and correlation analysis of Sigma1/<i>SIGMAR1</i> in prostate tumors. GSEA using Adipogenesis ROS Pathway Hallmark gene sets on localized tumors from TCGA (<b>A</b>; <a href="#bib60" target="_blank">60</a>) metastatic SU2C/PCF Dream Team (<b>B</b>; href="#bib61" target="_blank">61</a>). <b>C,</b> Heat map normalized enrichment scores primary, metastatic, or benign tissue utilizing TCGA, MSKCC, Team, FHCRC...
<p>Sigma1 small-molecule inhibition disrupts GSH ratios and increases ROS levels in LNCaP C4-2 cells. <b>A,</b> Quantification of CM-H<sub>2</sub>DCFDA signal per cell cells cultured CSS medium for 3 days treated with DHT (1 nmol/L) alone or combined 10 µmol/L IPAG the last 16 hours. Data are presented as mean ± SEM from three independent experiments, *, <i>P</i> < 0.05; **, 0.01; ***, 0.001; ****, 0.0001; ns, no significance....
<p>Sigma1 small-molecule inhibition disrupts GSH ratios and increases ROS levels in LNCaP C4-2 cells. <b>A,</b> Quantification of CM-H<sub>2</sub>DCFDA signal per cell cells cultured CSS medium for 3 days treated with DHT (1 nmol/L) alone or combined 10 µmol/L IPAG the last 16 hours. Data are presented as mean ± SEM from three independent experiments, *, <i>P</i> < 0.05; **, 0.01; ***, 0.001; ****, 0.0001; ns, no significance....
<p>Sigma1 KD suppresses DHT induced prostate cancer cell proliferation and tumor growth despite (or due to) increased autophagy. <b>A,</b><i>In vitro</i> assay of Sigma1 shRNA-transduced LNCaP C4-2 cells precultured in CSS medium for 3 days then treated 6 with 1 nmol/L DHT. Live were counted by Trypan blue exclusion at the start time course (day 0), treatment. Data are represented as fold induction over control shRNA day 0. Datapoints represent mean increase...
<p>Pharmacologic Sigma1 inhibitor eliminates DHT-induced AR-mediated LDs by lipophagy. Treatment with a small-molecule AR and ARV7 mediated LDs. Confocal image of HCS LipidTox stained (red) in LNCaP cells (<b>A</b>), C4-2 (<b>B</b>), VCaP (<b>C</b>) treated drug vehicle (DMSO), DHT (1 nmol/L, 3 days), treatment days) combined (IPAG, 10 µmol/L, added for the final 16 hours 3-day treatment), DAPI nuclei (blue). Quantification expressed as mean number...
<p>LDs as buffers of DHT induced ROS and promotes homeostasis. <b>A,</b> Confocal micrograph showing HCS LipidTox stained LDs in LNCaP cells cultured CSS containing medium for 3 days treated with DMSO (vehicle) 1 nmol/L alone or combined 2.5 mmol/L NAC days. <b>B,</b> LD quantification from A. Data represent per cell error bars SEM. *, <i>P</i> < 0.05; **, 0.01; ***, 0.001; ****, 0.0001. <b>C,</b> Quantification ROS, detected...
<p>Sigma1 KD suppresses DHT induced prostate cancer cell proliferation and tumor growth despite (or due to) increased autophagy. <b>A,</b><i>In vitro</i> assay of Sigma1 shRNA-transduced LNCaP C4-2 cells precultured in CSS medium for 3 days then treated 6 with 1 nmol/L DHT. Live were counted by Trypan blue exclusion at the start time course (day 0), treatment. Data are represented as fold induction over control shRNA day 0. Datapoints represent mean increase...
<div>Abstract<p>Lipid droplets (LD) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer, LD accumulation is associated with cancer aggressiveness, therapy resistance, poor clinical outcome. Prostate arises an androgen receptor (AR)-driven disease. Among its myriad roles, AR mediates...
<p>Pharmacologic Sigma1 inhibitor eliminates DHT-induced AR-mediated LDs by lipophagy. Treatment with a small-molecule AR and ARV7 mediated LDs. Confocal image of HCS LipidTox stained (red) in LNCaP cells (<b>A</b>), C4-2 (<b>B</b>), VCaP (<b>C</b>) treated drug vehicle (DMSO), DHT (1 nmol/L, 3 days), treatment days) combined (IPAG, 10 µmol/L, added for the final 16 hours 3-day treatment), DAPI nuclei (blue). Quantification expressed as mean number...
<p>LDs as buffers of DHT induced ROS and promotes homeostasis. <b>A,</b> Confocal micrograph showing HCS LipidTox stained LDs in LNCaP cells cultured CSS containing medium for 3 days treated with DMSO (vehicle) 1 nmol/L alone or combined 2.5 mmol/L NAC days. <b>B,</b> LD quantification from A. Data represent per cell error bars SEM. *, <i>P</i> < 0.05; **, 0.01; ***, 0.001; ****, 0.0001. <b>C,</b> Quantification ROS, detected...
<p>GSEA and correlation analysis of Sigma1/<i>SIGMAR1</i> in prostate tumors. GSEA using Adipogenesis ROS Pathway Hallmark gene sets on localized tumors from TCGA (<b>A</b>; <a href="#bib60" target="_blank">60</a>) metastatic SU2C/PCF Dream Team (<b>B</b>; href="#bib61" target="_blank">61</a>). <b>C,</b> Heat map normalized enrichment scores primary, metastatic, or benign tissue utilizing TCGA, MSKCC, Team, FHCRC...
<p>Sigma1 is required for DHT-induced AR-mediated LD accumulation in prostate cancer cells. <b>A,</b> Confocal micrograph showing LNCaP cells cultured CSS containing medium 3 days and then treated 1, 2, 3, 6 of DHT (1 nmol/L). HCS LipidTOX stained LDs (red). DAPI nuclei (blue). Quantification number per cell average area particles/cell. Data represent mean values from at least three independent determinations, error bars SEM. particle numbers lipid were quantified using...
<p>VCaP and C4-2 ROS LD data</p>
<p>LNCaP DHT + NAC Sigma1 shR proliferation</p>
<p>LDs as buffers of DHT induced ROS and promotes homeostasis. <b>A,</b> Confocal micrograph showing HCS LipidTox stained LDs in LNCaP cells cultured CSS containing medium for 3 days treated with DMSO (vehicle) 1 nmol/L alone or combined 2.5 mmol/L NAC days. <b>B,</b> LD quantification from A. Data represent per cell error bars SEM. *, <i>P</i> < 0.05; **, 0.01; ***, 0.001; ****, 0.0001. <b>C,</b> Quantification ROS, detected...
<p>GSEA and correlation analysis of Sigma1/<i>SIGMAR1</i> in prostate tumors. GSEA using Adipogenesis ROS Pathway Hallmark gene sets on localized tumors from TCGA (<b>A</b>; <a href="#bib60" target="_blank">60</a>) metastatic SU2C/PCF Dream Team (<b>B</b>; href="#bib61" target="_blank">61</a>). <b>C,</b> Heat map normalized enrichment scores primary, metastatic, or benign tissue utilizing TCGA, MSKCC, Team, FHCRC...
<p>Sigma1 KD triggers lipophagy. <b>A,</b> Confocal micrographs showing colocalization of GFP-LC3 (LC3, green) and HCS LipidTox labeled LDs (red) in Sigma1 shRNA-transduced LNCaP (GFP-LC3) cells that were serum-starved for 3 days treated with 1 nmol/L DHT alone or combined 10 bafilomycin A1 (BafA1) the final 8 hours prior to fixing cells. <b>B,</b> Inset from column 8, Merge A magnified view autophagosome LD (red). Overlapping, events indicated by white arrows....
<p>VCaP data</p>
<p>VCaP ROS and autophagy</p>
<p>LNCaP DHT + NAC Sigma1 shR proliferation</p>