A New Paradigm Coupling Stromal Microenvironment to Prostate Cancer Lipid and RNA Synthesis with Therapeutic Application
Abstract
Cancer cells adopt metabolic pathways that feature high rates of biosynthesis of molecules to fuel their growth. RNA polymerase I (Pol I) transcription is rate limiting for protein production and markedly activated by oncogenic stimuli and loss of tumor suppressors. Our seminal contributions show that targeting of Pol I transcription is actionable and has therapeutic benefit in preclinical cancer models, including prostate cancer. The discovery and identification of first-in-class small molecule Pol I inhibitors support new targeting stratagems and therapy approaches in cancer. Cells take up lipids and use them as building blocks for cellular structures, sources of energy, and precursors for hormonal synthesis. Lipid uptake occurs through caveolae, “omega-shaped” invaginations at the plasma membrane formed by caveolins (CAV) and polymerase I and transcript release factor (PTRF). In prostate cancer, PTRF is lost in the tumor stroma and correlates with poor prognosis. PTRF has a surprising dual function. It is essential for the formation of caveolae and also regulates Pol I transcription. This link and its impact have never been studied before. Prostate cholesterol content and synthesis equals that of liver. We provide evidence that suggests a linkage between Pol I transcription and lipid metabolism and show that combinatory therapies against these uniquely synergize to kill prostate cancer cells. We hypothesize that lipid uptake and Pol I transcription are coordinately regulated in response to needs of cellular energy and that PTRF integrates these activities. The objective of this study is to systematically analyze how Pol I and lipid metabolism pathways are linked and use new models to assess how the stroma affects tumor growth, phenotype, and dependency on the lipid metabolic and protein synthesis pathways. These studies outline a conceptually new approach that tests the impact of the stromal component on prostate cancer aggressiveness and treatment responses to a new combinatory approach that exploits cancer metabolic dependencies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710458
Entities
People
- Marikki Laiho
Organizations
- Johns Hopkins University
- United States Army