NADPH-Generating Enzymes as Potential Targets for Prostate Cancer Therapy
Abstract
The growth and replication of human cells is normally intricately regulated to ensure that only healthy cells are able to duplicate at the appropriate time. Cells that carry a damaged genome or other tumor-promoting alterations are eliminated from the replication pool through an elaborate cellular tumor suppression network. The central "hub" of this network is the preeminent tumor suppressor p53. The importance of p53 in tumor suppression is underscored by the observation that it is the most commonly mutated gene in human tumors, with its mutation being associated with 50%-70% of all cancers and 20%-30% of prostate cancer (PCa). In tumor cells with wild-type p53, it is commonly rendered inactive through mutations in p53 regulatory proteins. Inactivation of p53, either through a mutation in p53 itself or in its regulatory proteins, directly causes the formation and progression of PCa and other cancers. These observations raise two important issues. The first is how exactly p53 suppresses tumor formation. Although p53 is able to invoke a range of antiproliferative responses, recent studies have indicated that the regulation of cellular metabolism is a central component of p53-mediated tumor suppression. The metabolism in PCa cells, as in other cancer cells, is fundamentally altered to provide biomass for their proliferation and to protect them against oxidative damages inevitably experienced by cancer cells. Identification of p53-target genes that are involved in metabolism is crucial for understanding the molecular mechanisms of this preeminent tumor suppression. The second issue is how p53 is inactivated in tumor cells with wild-type p53. A better understanding of this issue will be instrumental in the development of a therapeutic strategy to reactivate p53 in these tumor cells. Genetic analyses using animal models have demonstrated that p53 reactivation halts tumor progression regardless of the stage of the tumor. Reactivation of p53 is especially attractive for PCa, given that a substantial number of them (70%-80%) have wild-type p53. In our preliminary studies, we have revealed a previously unexpected role of p53 in regulating two metabolic enzymes (known as malic enzymes). Both enzymes are important in generating NADPH, the cellular reducing equivalent that is used in various biosynthesis and antioxidant response. Equally interestingly, malic enzymes reciprocally regulate p53 and strongly suppress p53 activation. We found that these enzymes are also activated by the oncogene c-Myc, which is frequently upregulated in PCa and is important for PCa progression. We plan to investigate the role of the p53- and Myc-regulated malic enzymes in PCa biology and therapy. We will (1) examine the expression of malic enzymes and investigate their role in the progression of PCa, (2) determine the role of malic enzymes in metabolism that supports PCa growth, and (3) develop malic enzyme inhibitors and test their efficacy in PCa therapy using cell culture, xenograft, and transgenic models. This later will provide lead compound(s) to probe the feasibility of malic enzymes as drug targets for PCa therapy. Our studies will likely provide a strong rationale for targeting malic enzymes for the therapy of a wide range of PCa cells. In p53-mutant cells, inhibition of malic enzymes should blunt their hyperproliferative effect caused by the absence of p53. Similarly, inhibition of these enzymes should impair the growth of PCa with a hyperactive Myc. In p53-wild-type cells, blocking malic enzymes would lead to re-activation of p53 and the elimination of these prostate tumor cells. Thus, malic enzymes may be valuable targets for PCa at different stages and with different genetic alterations. The role of NADPH-generating metabolic enzymes in PCa cells is a salient unexplored area. Metabolic enzymes are among the most druggable targets, and the NADPH-generating malic enzymes play a critical role in p53- and Myc-me
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510678
Entities
People
- Xiaolu Yang
Organizations
- United States Army
- University of Pennsylvania