Ryanodine Receptor-1-Dependent Calcium Signaling Pathway as a Novel Tumorigenic Mechanism and Therapeutic Target of Ovarian Cancer
Abstract
Ovarian cancer (OC) is the fifth most common cause of cancer death in women worldwide. Advanced ovarian cancer (stages III and IV) accounts for most of the approximately 20,000 yearly new cases of epithelial ovarian cancer in the United States. Over 16,000 deaths per year in the United States are due to ovarian cancer, making it the most lethal gynecologic malignancy. Ovarian cancer, in particular high-grade serous ovarian cancer (HGSOC), is notable for initial chemosensitivity, with responding rates >75% to a combination of platinum and taxane chemotherapy following debulking surgery. Despite treatment have continued to improve in recent years, the recurrent rate is very high. In fact, around 80% of patients relapse within 12-24 months and die of progressive chemotherapy-resistant metastasis within 5 years. Hence, identifying new therapeutic targets and discovering unrecognized pathologic mechanisms of HGSOC progression are crucial for developing treatments against chemo-resistant ovarian cancer and prolonging patient survival. Intracellular Ca2+ signaling plays essential roles in regulating numerous cellular processes, including enzyme activity and metabolism; cell proliferation; contraction and motility; and gene expression. Ca2+ signals originating from various types of Ca2+ channels and transporters in different subcellular compartments exert their effects through modulation of specific Ca2+-sensitive effectors in a global or local manner. There is increasing evidence suggesting that aberrant Ca2+ signals and remodeling of Ca2+ signaling mechanisms occur in cancer cells and contribute significantly to the malignant phenotypes. By using survival correlation analysis of ovarian cancer patient databases, we have identified for the first time that an increase in ryanodine receptor-1 (RYR1), a Ca2+ permeating channel, within ovarian cancer cells is associated with significant reduction of patient’s survival time. This observation is confirmed in an independent set of ovarian cancer samples collected in the MD Anderson Cancer Center. RYR1 is a type of Ca2+ channel originally found in skeletal muscles. It is responsible for releasing Ca2+ from Ca2+ stores within the cells to elicit muscle contraction and other cellular functions. In normal ovarian epithelial cells or fallopian tubular epithelial cells, Ca2+ release is controlled mainly by another type of Ca2+ channel, called inositol trisphosphate receptor (IP3R), and the expression of RYR1 is minimal. Our analysis showed that the increase in RYR1 expression is associated with a reduction in IP3R expression in the ovarian tumor samples. It is well recognized that IP3R-mediated Ca2+ release is important for regulating gene transcription, mitochondrial functions, and mobilization of extracellular Ca2+ influx. The dramatic shift in Ca2+ release mechanism from IP3R to RYR in ovarian cancer cells may disrupt normal Ca2+ homeostasis and facilitate malignant transition. Using a mouse model and ovarian cancer cells in culture, we have evidence that inhibition of RYR1 suppresses cancer cell activity and tumor progression. However, the cellular and molecular mechanisms through which RYR1 affects the cancer cell activity are unclear, and its important contribution to cancer development has not been examined. In this proposal, we will apply a combination of state-of-the-art confocal imaging technique, organelle specific Ca2+ biosensors, and molecular biology techniques to characterize the RyR1-dependent Ca2+ signals in subcellular compartments of HGSOC cells and patient-derived xenograft cells. We will determine the interactions of RYRs with mitochondria, membrane ion channels, and different signaling pathways to evaluate their contributions to cancer cell proliferation, migration, invasion, apoptosis, and gene expression. We will also use different mouse models of ovarian cancer to determine the importance of the increased expression of RYR1 in OC progression an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210169
Entities
People
- James Sham
Organizations
- Johns Hopkins University
- United States Army