Purinergic Signaling and Inflammation in Prostate Cancer Racial Disparities
Abstract
Prostate cancer (PCa) is the second-leading cause of cancer death in American men. Chronic inflammation is implicated as a major risk factor for PCa, and genes involved in inflammatory pathways are reported as more prevalent in tumors from African American (AA) versus Caucasian American (CA) men. This finding may be of significance in deciphering the distinct discrepancy in mortality rates that are two to three times greater among AA men than among CA men. It is imperative that we understand the key players involved in prostate inflammation, and the mechanisms involved in PCa initiation, in order to facilitate improved prognostics and early targeted therapies. ATP is a well-known unit of energy within the cell. Over the last few decades, it has been reported that ATP may be released outside of the cell as a result of cell stress, injury, or death. This extracellular ATP may then activate receptors known as P2 purinergic receptors eliciting a series of biological responses including inflammation, cell proliferation, and the increased ability of cells to migrate and invade other sites ? all hallmarks of cancer. As such, P2 purinergic receptors have recently been studied in the context of cancer. Currently, there are multiple P2 purinergic receptor antagonists in clinical trials or that are Food and Drug Administration-approved for treatment of other diseases. The objective of this proposal is to decipher the role of purinergic signaling in PCa such that we may unveil a subset of patients for which targeted therapies are successful, particularly among AA men. We hypothesize that prostate cell injury and death result in ATP release, which drives inflammation, causing dysregulation of P2 purinergic receptors. P2 receptor dysregulation may, in turn, promote cell migration and invasion, thus facilitating prostate cancer development. We will test this hypothesis in the following aims. Specific Aim 1: Evaluation of P2 purinergic receptor expression in PCa and matched benign tissues from AA and CA men. Specific Aim 2: Determine whether P2 purinergic receptor activation promotes prostate cell transformation to cancer cells and explore P2 purinergic signaling roles in inflammation. We will use various experimental techniques to measure P2 purinergic receptor expression levels in cancer and correlate expression levels with tumor grade, race, and survival. This will help ascertain whether these receptors may act as biomarkers, which are useful in predicting clinical outcomes in patients with PCa. Furthermore, we will test the various functional roles of these receptors in human PCa cell lines and a mouse model of inflammation to determine whether activation or blockade of a specific receptor may prevent PCa development or improve clinical outcomes. Ultimately, we seek to better understand how chronic inflammation may contribute to PCa development, in the context of purinergic signaling and to identify new targets for early therapies. Considering that many pharmacologic agents have already been developed and tested to target multiple P2 purinergic receptors, it is likely that purinergic signaling-based therapy may achieve patient-related outcomes within the next decade. Our studies will help identify the patients more likely to benefit from these therapies, and we anticipate that this subset will be substantial owing to the high prevalence of prostate inflammation in PCa patients. The proposed research provides experience to the Principal Investigator (PI) required to gain the necessary skills, competence, and expertise to pursue a career as a tenure-track independent PCa researcher. The study requires the use of patient samples, cell lines, and animal models using a wide array of technical skills. Furthermore, the researcher development plan proposed includes participation in journal clubs, research seminars, scientific meetings, and national conferences that serve as academic and professional deve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710292
Entities
People
- Janielle P Maynard
Organizations
- Johns Hopkins University
- United States Army