Glucose Metabolism in the Progression of Prostate Cancer

Abstract

Prostate cancer is one of the most common types of cancer in western country males but the mechanisms involved in the transformation processes have not been clearly elucidated. Alteration in cellular metabolism in cancer cells is recognized as a hallmark of malignant transformation, although it is becoming clear that the biological features of metabolic reprogramming not only differ in different cancers, but also among different cells in a type of cancer. Normal prostate epithelial cells have a peculiar and very inefficient energy metabolism as they use glucose to synthesize citrate that is secreted as part of the seminal liquid. During the transformation process, prostate cancer cells modify their energy metabolism from inefficient to highly efficient, often taking advantage of the interaction with other cell types in the tumor microenvironment that are corrupted to produce and secrete metabolic intermediates used by cancer cells in catabolic and anabolic processes. We recapitulate the metabolic transformations occurring in the prostate from the normal cell to the metastasis, highlighting the role of the microenvironment and summarizing what is known on the molecular mechanisms involved in the process.

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

“…It is established, that PCa tumorigenesis is accompanied by enhanced TCA/OXPHOS activity (Costello and Franklin, 2006, Costello et al, 1997, Cutruzzolà et al, 2017. Our data suggest a STAT3-dependent downregulation of TCA/OXPHOS, supporting the notion of a tumor suppressive function of STAT3 in primary PCa.…”

“…The generation of mitochondrial adenosine triphosphate (ATP) through aerobic respiration via TCA/OXPHOS is the primary source of energy in most normal cells (Hanahan andWeinberg, 2011, Stacpoole, 2017). Prostate epithelial cells, however, are characterized by a physiological downregulation of TCA/OXPHOS, caused by citrate secretion and zinc accumulation in the cell (Costello and Franklin, 2006, Costello et al, 1997, Cutruzzolà et al, 2017. This is due to the highly specialized role of prostate epithelial cells, which excrete citrate-rich prostatic fluid (Costello et al, 1997).…”

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

“…Strikingly, the majority of those genes were significantly downregulated in CDK12 -mutant mCRPC (Figure S4I). Although the shift from oxidative to glycolytic metabolism (Warburg effect) is a hallmark of many cancer types (Vander Heiden et al, 2009), it is not a characteristic of most prostate cancers (Cutruzzola et al, 2017). …”

The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

“…The prostatic fluid contains high levels of citrate because of the inhibition of m-aconitase, a tricarboxylic acid (TCA) cycle enzyme that converts citrate into isocitrate. 26 Glucose metabolism has not been considered as important as glutamine or lipid metabolism in PCa progression, being the reason why it has been less studied. Since the TCA cycle is somehow compromised in the prostate gland, glycolysis is then favored (Fig.…”

“…25 Lactate is consumed by OXPHOS-dependent PCa cells, having a role in redox homeostasis and angiogenesis. 26 Glucose metabolism has not been considered as important as glutamine or lipid metabolism in PCa progression, being the reason why it has been less studied. Several candidates have been proposed as potential metabolic targets.…”