Project 466967

The Prorenin Receptor (PRR) is a single-spanning transmembrane protein. It is cleaved to form an N-terminal secreted fragment called secreted PRR (sPRR), and a short transmembrane C-terminal fragment called M8.9. sPRR is well recognized as an important component of the renin angiotensin system for the regulation of blood pressure.Recently, the lab screened for secreted factors affected by the loss of PTEN, a common mutation found in breast and prostate cancers. We demonstrated that sPRR was increased in cancers with PTEN loss, and higher amount of sPRR correlates with tumor size. We have genetically engineered mice with a point mutation in the PRR gene (PRRpm) preventing the cleavage of PRR into sPRR and M8.9. This data suggests that sPRR may play a role as a metabolic regulator leading to the hypothesis the secretion of sPRR by cancer cells may promote a metabolic shift to promote tumor growth.To test this, first we will generate and purify recombinant sPRR (rsPRR) with metal affinity resin. We will then initially focus our study on LNCaP cells since we have studied PRR extensively in them. Using the Agilent Seahorse instrument in the Goodman Cancer Institute, we will metabolic signatures the LNCaP cells treated with or without rsPRR.We have isolated mouse embryonic fibroblasts (MEFs) from both PRRpm and wild-type littermates and will look for metabolic changes in the mutant cells treated with or without rsPRR with the Seahorse.To test the relationship between cellular transformation and sPRR, we will perform transformation assays by lentiviral transduction using the MEFs. If sPRR is shown to be an important metabolic regulator in cancer, neutralization of sPRR in the blood could help slow tumor growth and be a viable treatment option for cancer patients.