Glutathione Metabolism in Renal Cell Carcinoma Progression and Implications for Therapies

Abstract

A significantly increased level of the reactive oxygen species (ROS) scavenger glutathione (GSH) has been identified as a hallmark of renal cell carcinoma (RCC). The proposed mechanism for increased GSH levels is to counteract damaging ROS to sustain the viability and growth of the malignancy. Here, we review the current knowledge about the three main RCC subtypes, namely clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC), at the genetic, transcript, protein, and metabolite level and highlight their mutual influence on GSH metabolism. A further discussion addresses the question of how the manipulation of GSH levels can be exploited as a potential treatment strategy for RCC.

Keywords: Renal cell carcinoma (RCC); cancer therapy; chromophobe RCC; clear cell RCC; glutathione (GSH) metabolism; papillary RCC; reactive oxygen species (ROS).

Figure 1

Schematic overview of glutathione (GSH) metabolism and the targeting sites of inhibitors. Color codes are defined as follows: black = enzymes or transporters; red = metabolites; blue = inhibitors. GGT: γ-glutamyl transferase; xCT: solute carrier family 7 member 11, a cystine-glutamate antiporter; GLS1: glutaminase 1; GCL: glutamate cysteine ligase; GSS: glutathione synthetase. GSSG: glutathione oxidized form; ROS: reactive oxygen species.

Figure 2

The availability of the precursor amino acids that influence GSH synthesis. Color codes are defined as follows: black = enzymes or transporters; red = metabolites. SLC38A1/2: solute carrier family 38 member 1 and 2, glutamine transporters; GLUD: glutamate dehydrogenase; SAM: S-adenosyl methionine; SAH: S-adenosyl homocysteine.