27-Hydroxycholesterol Impairs Plasma Membrane Lipid Raft Signaling as Evidenced by Inhibition of IL6–JAK–STAT3 Signaling in Prostate Cancer Cells
Abstract
We recently reported that restoring the CYP27A1–27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti–prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6–JAK–STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6–JAK–STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2020
- Source ID
- 10.1158/1541-7786.mcr-19-0974
Entities
People
- Adela Ramirez-torres
- Erick Maravilla
- Everardo Macias
- Gloria C Galvan
- James Turkson
- Jen-Tsan A Chi
- Junhee Yoon
- Lucy M. Driver
- Mahmoud Alfaqih
- Mariana Reis Sobreiro
- Matthew S. Behrove
- Michael R Freeman
- Mirja Rotinen
- Sergio Sanders
- Shweta Dambal
- Stephen J. Freedland
- Sungyong You
- Tijana Jovanovic-Talisman
Organizations
- City of Hope National Medical Center
- Duke University
- Durham VA Medical Center
- United States Department of Defense