AMPK as a Novel Host Factor Regulating Ovarian Cancer Progression
Abstract
While advances have been made in understanding the genetic and pathological biology of ovarian cancer, not much is known about how host environment can regulate the process of ovarian cancer growth. Recently we published that energy intake balance modulates ovarian cancer progression and metastasis using a preclinical mouse model, which was also corroborated by another group in a genetic preclinical model of ovarian cancer. These reports demonstrate the likely possibility that host environment can alter ovarian tumor growth, metastasis, and outcome. During our study, we found the metabolic enzyme AMPK (Adenosine Monophosphate activated Kinase) to play an important part in regulating ovarian cancer progression. AMPK, the central regulator of energy metabolism in all eukaryotic cells, is also the target of the diabetic drug metformin. We and others have extensively demonstrated the anti-growth effects of metformin against ovarian cancer and various other tumors. To understand the role of AMPK in ovarian cancer progression, we generated mouse syngeneic ovarian tumors (ID8 cell line) in wild-type (Wt) and AMPK knockout (KO) mice and found KO mice to show faster tumor growth, severe metastasis, and shorter survival. Our preliminary data indicate that the aggravated ovarian tumors seen in absence of AMPK are due to altered immune cells called the myeloid-derived suppressor cells (MDSCs). The MDSCs are immunosuppressive cells that block the T-cell function, hamper the effect of chemotherapy, and compromise the new immunotherapies, which consequently allows relentless tumor growth. Our preliminary findings show that AMPK deficiency results in hyper-immunosuppressive MDSCs that are capable of greater suppression of T cells, translating to a decreased anti-tumor immune response. In the current proposal, we are hypothesizing that loss of AMPK alters the energy metabolism of MDSCs by changing their preference of energy pathway, which makes them hyper-immunosuppressive. Recently the metabolic shifts from oxidative phosphorylation/fatty acid oxidation towards glycolysis energy pathways as a means of executing their effector functions has been recognized in various immune cells. Here we proposed three aims: to define the role of hyper-immunosuppressive MDSCs in promoting ovarian cancer growth (Aim 1); to comprehensively elucidate the metabolic mechanism responsible for the hyper-immunosuppressive nature of MDSCs with AMPK deficiency that allows them to switch to an alternate energy source (Aim 2); and to validate the relationship between AMPK expression, MDSC immunosuppression ability and its impact on patient outcome by correlating the expression of these proteins in patient tumor tissue (tissue microarrays) and clinical parameters (Aim 3). The impact of defining the AMPK-MDSC energy metabolism and regulation of MDSC immunosuppressive function lies in discovering a more effective therapeutic approach towards treatment of ovarian cancer using metabolic drugs or intervention approaches. AMPK deficiency in host can be reflected in patients with sedentary lifestyle, high nutrition intake, or aging, as these conditions negatively affect AMPK activity, resulting in an increased immunosuppressive host environment. Our recent study clearly showed that modulation of energy intake alters the tumor growth and metastasis in ID8 bearing mice, suggesting that the host can regulate the outcome of ovarian tumor. Thus, studying the metabolic mechanism behind the immunosuppressive mediators like MDSCs will likely lead to identification of new targetable pathways that can ameliorate and allow anti-tumor immunity to work effectively. This knowledge becomes even more important in the context of the recent advent of immunotherapies. As most of the current immunotherapies are based on T cells, they are susceptible to being compromised by the immunosuppressive tumor microenvironment led by MDSCs and associated mediators. Therefore, targeti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710170
Entities
People
- Ramandeep Rattan
Organizations
- Henry Ford Health
- United States Army