Prostate Cancer Cell Growth: Role of Neurotensin in Mediating Effect of Dietary Fat and Mechanism of Action
Abstract
Aims: (a) study mechanism of neurotensin(NT)-enhanced prostate cancer(PC)growth; (b)test if NT released from gut contributes to the PC-growth effect of fatty diets. In PC3 cells, NT transactivated EGF receptor (EGFR), liberating HB-EGF from cell-surface by a protease-dependent and PKC-dependent mechanism. Activation of EGFR led to activation of MAP-kinase, P13-kinase, AKT and p7O-S6-kinase, and in 24 hrs to enhanced DNA synthesis. NT and EGF stimulated cellular release 3H-AA. Inhibitors of Lipoxygenase (LOX) blocked basal and NT- induced DNA synthesis, suggesting that EGF and NT acted by way of PLA2, S-LOX and 12-LOX (present by western blot). NT receptor function was modulated by antioxidants and calcium channel blockers, which indirectly blocked inositol phosphate formation. In the presence of a Gs stimulus, NT enhanced cAMP production, giving an inhibition of DNA synthesis. Thus, NT effects involve EGFR, protein kinases, LOXs and adenylyl cyclases, and its effects depend on the hormonal milieu. An NT-knockout-nude mouse strain was developed and PC3 cell xenografts were found to grow faster in NT(++) mice than in NT(--) mice given a high fat diet. Our results suggest that NT released during fat ingestion stimulates PC growth via effects involving EGFR, protein kinases, LOXs and calcium channels.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2004
- Accession Number
- ADA431644
Entities
People
- Robert E. Carraway
Organizations
- University of Massachusetts Medical School