Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming
Rajeev Mishra, … , Edwin M. Posadas, Neil A. Bhowmick
Rajeev Mishra, … , Edwin M. Posadas, Neil A. Bhowmick
Published July 26, 2018
Citation Information: J Clin Invest. 2018;128(10):4472-4484. https://doi.org/10.1172/JCI99397.
View: Text | PDF
Research Article Cell biology Metabolism Article has an altmetric score of 114

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

  • Text
  • PDF
Abstract

Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified a Ras inhibitor, RASAL3, as epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In an orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.

Authors

Rajeev Mishra, Subhash Haldar, Veronica Placencio, Anisha Madhav, Krizia Rohena-Rivera, Priyanka Agarwal, Frank Duong, Bryan Angara, Manisha Tripathi, Zhenqiu Liu, Roberta A. Gottlieb, Shawn Wagner, Edwin M. Posadas, Neil A. Bhowmick

×

Figure 4

Stromal-derived glutamine induces mitochondrial bioenergetics and PCa neuroendocrine differentiation.

Options: View larger image (or click on image) Download as PowerPoint
Stromal-derived glutamine induces mitochondrial bioenergetics and PCa ne...
(A) Kinetic OCR response in CWR22Rv1 cells exposed to 2 mM glutamine and rotenone along with antamycin. The OCR values were normalized to total protein. (B) Bioenergetic parameters of CWR22Rv1 cells incubated with WT or RasV12 fibroblast CM in the presence or absence of GPNA. Left: OCR trace for all 3 groups. Right: basal OCR, ATP, and maximal respiration (max. resp.) are separately represented. (C) CWR22Rv1 cells were cocultured with WT and RasV12 mouse prostatic fibroblasts in 3D and treated with vehicle, BPTES, or GPNA. Box plot of epithelial proliferation was measured by FACS analysis of EpCAM+Ki67+ cells. Statistical analysis was performed using 2-tailed Student’s t test. (D) Phosphorylated mTOR and FOXM1 protein levels were measured in CWR22Rv1 cells incubated with either WT or RasV12 CM for 3 days. (A–D) Representative data from 3 independent experiments are shown. (E) STRING analysis of a PCa neuroendocrine gene signature demonstrates direct or indirect interactions with FOXM1. (F) Heatmap summarizing the quantitative PCR results comparing CWR22Rv1 expression of neuroendocrine marker genes following treatment with CM from WT or RasV12 fibroblasts or (G) l-glutamine (Gln) alone or l-glutamine in combination with rapamycin relative to vehicle. rap, rapamycin. Two-way ANOVA analysis indicates overall P value with F test showing P < 0.0001 for both experiments (n = 3; F, G). Epithelial and stromal cells were grown in either glutamine-free DMEMF12 or RPMI media. Data are represented as mean ± SD. *P < 0.05; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 16 news outlets
Posted by 10 X users
On 3 Facebook pages
89 readers on Mendeley
See more details