Prostate Cancer Energetics and Biosynthesis

Abstract

Cancers must alter their metabolism to satisfy the increased demand for energy and to produce building blocks that are required to create a rapidly growing tumor. Further, for cancer cells to thrive, they must also adapt to an often changing tumor microenvironment, which can present new metabolic challenges (ex. hypoxia) that are unfavorable for most other cells. As such, altered metabolism is now considered an emerging hallmark of cancer. Like many other malignancies, the metabolism of prostate cancer is considerably different compared to matched benign tissue. However, prostate cancers exhibit distinct metabolic characteristics that set them apart from many other tumor types. In this chapter, we will describe the known alterations in prostate cancer metabolism that occur during initial tumorigenesis and throughout disease progression. In addition, we will highlight upstream regulators that control these metabolic changes. Finally, we will discuss how this new knowledge is being leveraged to improve patient care through the development of novel biomarkers and metabolically targeted therapies.

Keywords: AR; Imaging; Metabolism; Prostate cancer.

Figure 1.. Evolution of prostate cancer metabolism.

Normal prostate epithelial cells exhibit a truncated TCA cycle that results in the increased production and secretion of citrate. During the initial transformation towards malignancy, intracellular concentrations of zinc drop causing a derepression of aconitase (the enzyme that converts citrate to isocitrate) and subsequent increased flux through the TCA cycle. Concurrently, cancer cells start to exhibit aerobic glycolysis, elevated glutaminolysis and increased flux through the hexosamine biosynthetic and pentose phosphate pathways. Interestingly, another hallmark of prostate cancers is the concurrent increases in both de novo lipogenesis and fatty acid oxidation. When prostate cancers progress into the late stages of the disease, the classic Warburg effect becomes more pronounced while some pathways, such as the hexosamine biosynthetic pathway, may reverse. While the initial metabolic transformation of prostatic cells has been well described to result from alterations such as the decreases in intracellular zinc concentrations, many of the drivers of the metabolic changes that occur in advanced prostate cancer remain poorly understood. Shown here is only a brief snapshot of central carbon metabolism.

Figure 2.. Continued evolution of prostate cancer metabolism.

The emergence of a new subtype of advanced prostate cancer termed neuroendocrine-like prostate cancer (NEPC; also commonly referred to as small cell-like prostate cancer (SCPC) and/or aggressive variant prostate cancer (AVPC) depending on its features) raises new questions regarding the metabolic phenotype of this form of the disease. Is the metabolism of NEPCs similar to that of advanced adenocarcinomas? Are there unique features that could be exploited for detection or treatment purposes?