Androgen receptor (AR) signaling is an essential factor for the progression of prostate cancer. In prostate cancer, androgens bind to the receptor to activate a cascade of events that lead to aberrant cell growth. Consequently, hormone ablation therapies are the standard of care for progressive malignancies. Unfortunately, these treatments are only effective for a ~1-2 year period after which prostate cancer reoccurs in the castration-resistant form. There is currently no cure for this advanced stage of the disease. Although this stage of the disease is unaffected by existing hormone therapies, AR-regulated pathways are still active and continue to promote cancer progression. Thus, the processes downstream of the receptor, together with other oncogenic signals, remain viable targets for therapeutic intervention. Glycolysis is a well-studied, established way that cancer cells use glucose as an energy source. Conversely, the role of glutamine metabolism in prostate cancer progression is far less clear. Glutamine metabolism is utilized by the cell to balance of the level of carbon and nitrogen. A master regulator of glutamine metabolism is the canonical oncogene Myc. While Myc is best known for its ability to regulate the cell cycle, it has also been demonstrated in other cancers to regulate glutaminolysis, a metabolic process in which the cell uptakes glutamine and converts it into ?-ketoglutarate and beyond to satisfy its metabolic needs. Preliminary data we have generated indicate that AR signaling promotes prostate cancer, in part, through increasing glutaminolysis. These data combined with existing clinical data suggest AR signaling, Myc, and glutamine metabolism may coordinate to drive prostate cancer progression. As such, understanding their relationship could lead to novel glutamine-directed therapeutics for the treatment of prostate cancer. Our long-term goal is to develop new metabolic-based therapeutic approaches for the detection and treatment of cancer. The primary goal of this application is to use a combination of preclinical models to understand the relationship(s) between AR signaling and glutamine metabolism to determine whether their intersection represents a viable therapeutic target. The central hypothesis is that AR signaling promotes prostate cancer cell growth through Myc-mediated glutamine metabolism. To test this hypothesis, two specific aims are proposed.
In Aim 1, a combination of cellular assays will be used to define the roles of AR and Myc in glutamine metabolism in vitro.
In Aim 2, intact and castrate mouse models of prostate cancer will be used to test whether specific aspects of AR and Myc signaling that regulate glutamine metabolism could represent novel therapeutic targets in vivo. From this research it is expected that targeting glutamine transporters will emerge as a novel way to combat prostate cancer. Further, data generated from this research could also provide the impetus to test whether glutamine analogs could be used as tracers for the detection of prostate cancer and if glutamine transporter expression levels may also have utility as prognostic markers.
Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer-related deaths in US men. This study will identify and validate cellular processes that drive this prevalent disease. Understanding how prostate cancer cells utilize glutamine will enable future research geared towards developing mechanistically new therapeutic strategies to both detect and treat prostate cancer after standard care methods fail.
|White, Mark A; Lin, Chenchu; Rajapakshe, Kimal et al. (2017) Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer. Mol Cancer Res 15:1017-1028|
|Shafi, Ayesha A; Putluri, Vasanta; Arnold, James M et al. (2015) Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells. Oncotarget 6:31997-2012|