Ryanodine Receptor-1 Dependent Calcium Signaling Pathway as a Novel Tumorigenic Mechanism and Therapeutic Target of Ovarian Cancer
Abstract
This award tests the hypothesis that ryanodine receptor-1 (RYR1) upregulation in high grade serous ovarian cancer (HGSOC) represents an aberrant shift in the modality of Ca2+ signaling, which contributes to the changes in cellular metabolism and signal transduction, leading to the malignant phenotype of proliferation, migration and invasion; RYR1 overexpression is associated with poor patient survival, and disruption of this mechanism can be effective for ovarian cancer treatment. In this funding period, we completed experiments in several major goals and found that (1) RYR1 overexpression inOVCA432 and OVCA433 cells caused significant increase in resting [Ca2+] compared to the control HOSE cells, indicative of altered Ca2+ homeostasis, (2) activation of RYR receptor induced Ca2+ release was enhanced in HGSOC cells, (3) RYR1upregulation is associated with down-regulation of IP3R expression and suppression of IP3R-dependent Ca2+ release signals, indicative of a switch of modality of Ca2+ signaling from IP3Rs to RYRs, (4) RYR1-dependent store-operated Ca2+ entry is enhanced in HGSOC cells, (5) the enhanced proliferation and migration in HGSOC cells were suppressed, while apoptosis as enhanced by shRNA knockdown of RYR1 and the RYR1 antagonist dantrolene, (6) dantolene treatment significantly suppressed OC development in the athymic nude mouse model.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2023
- Accession Number
- AD1203909
Entities
People
- James S. Sham
Organizations
- Johns Hopkins University