Cell metabolism: an essential link between cell growth and apoptosis

Abstract

Growth factor-stimulated or cancerous cells require sufficient nutrients to meet the metabolic demands of cell growth and division. If nutrients are insufficient, metabolic checkpoints are triggered that lead to cell cycle arrest and the activation of the intrinsic apoptotic cascade through a process dependent on the Bcl-2 family of proteins. Given the connections between metabolism and apoptosis, the notion of targeting metabolism to induce cell death in cancer cells has recently garnered much attention. However, the signaling pathways by which metabolic stresses induce apoptosis have not as of yet been fully elucidated. Thus, the best approach to this promising therapeutic avenue remains unclear. This review will discuss the intricate links between metabolism, growth, and intrinsic apoptosis and will consider ways in which manipulation of metabolism might be exploited to promote apoptotic cell death in cancer cells. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.

Figure 1. Growth factor signals and nutrient availability determine cell fate

As growth factor signals increase the drive for cell proliferation and metabolic demands increase. Availability of nutrients determines if sufficient resources are present to support cell survival and growth. If insufficient nutrients are available, cells undergo apoptosis. These metabolic checkpoints to link nutrients to cell cycle arrest and apoptosis are critical elements to maintain tissue homeostasis and prevent disease.

Figure 2. Growth factor or oncogene-stimulated cell metabolism

Through regulation of signaling pathways such as Akt and Myc growth factors promote glucose and glutamine uptake for glycolysis and glutaminolysis. Inhibition with these metabolic pathways can lead to cell death but precise links between specific metabolic pathways and Bcl-2 family proteins are poorly understood.

Figure 3. Model of how metabolic stress may regulate Bcl-2 family proteins to promote apoptosis

Growth factor deprivation reduces nutrient uptake and anoxia or glucose insufficiency cause direct metabolic stress. In each case, the anti-apoptotic protein Mcl-1 and pro-apoptotic BH3-only proteins are key mediators of metabolic checkpoints to initiate Bax-mediated cytochrome c release and apoptosis. Specific details of regulations are uncertain and indicated by “?”.