Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

Abstract

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin-proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.

Keywords: anaerobic glycolysis; anticancer; hypoxia; small molecules; ubiquitin–proteasome system (UPS).

Figure 1

Differences in glycolysis pathways between normal cells and cancer cells. (A) In the presence of oxygen, normal cells produce carbon dioxide up to 38 ATPs per glucose molecule through glycolysis, TCA cycle, and electron transport system. In a hypoxic environment, pyruvates are accumulated without going through the TCA cycle. These accumulated pyruvates in the muscle tissue are converted to lactic acid and only produce 2 ATPs. (B) Cancer cells only use the glycolysis process, regardless of the presence or absence of oxygen; 2 ATPs are produced per glucose molecule and, therefore, compared to normal cells, more glucose is required to obtain energy.

Figure 2

The schematic diagram of the ubiquitin–proteasome system (UPS). The ATP-activated E1 enzyme binds to glycine at the end of ubiquitin. The E1 enzyme delivers the ubiquitin to the E2 enzyme. The E2 enzyme binds to the E3 enzyme (E3 ligase) bound to the substrate protein. Ubiquitin linked to the E2 enzyme moves to the substrate protein. By repeating this process, several ubiquitins form a polyubiquitin chain, and the substrate is degraded through the 26S proteasome. Deubiquitinating enzyme (DUB) acts in opposition to the E3 ligase, which links ubiquitin to the substrate protein.

Figure 3

The schematic model for the Warburg effect modulated by DUBs and their substrates. The black arrow indicates direct stimulatory/inhibitory modification, and the blue arrow indicates transcriptional stimulatory modification. The blue circles represent the factors of the Warburg effect, and the gray square boxes represent their DUBs.