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Review
. 2016:327:43-87.
doi: 10.1016/bs.ircmb.2016.06.006. Epub 2016 Jul 30.

Metabolic Regulation of Apoptosis in Cancer

K Matsuura  1 , K Canfield  2 , W Feng  3 , M Kurokawa  4
Affiliations
Review

Metabolic Regulation of Apoptosis in Cancer

K Matsuura et al. Int Rev Cell Mol Biol. 2016.

Abstract

Apoptosis is a cellular suicide program that plays a critical role in development and human diseases, including cancer. Cancer cells evade apoptosis, thereby enabling excessive proliferation, survival under hypoxic conditions, and acquired resistance to therapeutic agents. Among various mechanisms that contribute to the evasion of apoptosis in cancer, metabolism is emerging as one of the key factors. Cellular metabolites can regulate functions of pro- and antiapoptotic proteins. In turn, p53, a regulator of apoptosis, also controls metabolism by limiting glycolysis and facilitating mitochondrial respiration. Consequently, with dysregulated metabolism and p53 inactivation, cancer cells are well-equipped to disable the apoptotic machinery. In this article, we review how cellular apoptosis is regulated and how metabolism can influence the signaling pathways leading to apoptosis, especially focusing on how glucose and lipid metabolism are altered in cancer cells and how these alterations can impact the apoptotic pathways.

Keywords: BCL-2 family; caspase; cell death; ceramide; glucose; hypoxia; lipids; p53.

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Figures

Figure 1
Figure 1
Structure of caspases. All caspases have a large subunit and a small subunit, which are indispensible for protease activity. Caspases can be divided into two types: initiators and effectors. While the effector caspases (i.e., caspases-3, -6, and -7) have a short prodomain, the initiators have a long prodomain which plays a crucial role for proximity-induced activation mediated by the interaction with adaptor proteins. Caspases-1, -4, -5, and -12 are implicated in inflammation, whereas caspases-8/-10 and caspases-2/-9 initiate the extrinsic and intrinsic apoptosis pathways, respectively. CARD; caspase recruitment domain, DED; death effector domain.
Figure 2
Figure 2
Apoptosis pathways. Intrinsic stress (e.g., DNA damage and metabolic stress) induces the expression and/or activation of proapoptotic BH3-only proteins, which either suppress antiapoptotic BCL-2 family proteins or directly activate BAX and BAK (Fig. 3). BAX and BAK induce mitochondrial outer membrane permeabilization (MOMP). Upon MOMP, cytochrome c (Cyt. c) is released from the mitochondrial intermembrane space. The release of cytochrome c triggers the formation of apoptosome in the cytoplasm, which recruits and activates caspase-9. Active caspase-9 cleaves and activates effector caspases, caspases-3 and -7. Intrinsic stress also engages the formation of PIDDosome which is composed of PIDD, RAIDD, and caspase-2. Through proximity-induced activation, casapse-2 becomes active and cleaves BID. Once cleaved, BID (tBID: truncated BID) becomes an active BH3-only protein. Extrinsic stress (e.g., TNF and TRAIL) is mediated through the death receptor, which forms the DISC (Death Inducing Signaling Complex) with FADD and caspase-8. Active caspase-8 directly cleaves and activates effector caspases or triggers the intrinsic apoptosis pathway through BID cleavage. TNF; tumor necrosis factor, TRAIL; TNF-related apoptosis-inducing ligand.
Figure 3
Figure 3
Regulation of BCL-2 family proteins. BCL-2 family proteins are divided into three groups: antiapoptotic BCL-2 family proteins (BCL-2, BCL-W, BCL-xL, MCL-1, and A1), proapoptotic multidomain proteins (BAX, BAK, and BOK), and proapoptotic BH3-only proteins (BIM, PUMA, BID, BAD, and NOXA).
Figure 4
Figure 4
The indirect activator model and the direct activator-derepressor model. In the indirect activator model, activation of BAX and BAK can be directly suppressed by any of the antiapoptotic BCL-2 family proteins. Upon apoptotic stimuli, BH3-only proteins are induced and occupy the antiapoptotic BCL-2 family proteins, which will release BAX and BAK to form active pore-forming oligomers. In the direct activator-derepressor model, the activation of BAX/BAK is prevented by the suppression of BH3-only proteins by the antiapoptotic BCL-2 family proteins. Upon induction of BH3-only proteins, derepressors (e.g., BAD and NOXA) competitively bind to antiapoptotic BCL-2 family proteins (e.g., BID, BIM, PUMA), which will release direct activators and allow for subsequent oligomerization of BAX and BAK.
Figure 5
Figure 5
The interaction between antiapoptotic BCL-2 family proteins and proapoptotic BCL-2 family members. BCL-2 and BCL-xL interact with all of the BH3-only proteins except for NOXA, while MCL-1 can bind to all of the BH3-only protein except for BAD. Of note, BIM, PUMA, and BID are capable of interacting with all of the antiapoptotic BCL-2 family proteins. Furthermore, BIM, PUMA, and BID can directly activate BAX and BAK in the direct activator–derepressor model.
Figure 6
Figure 6
Metabolism pathways. Extracellular glucose is transported into a cell through the glucose transporter (GLUT), phosphorylated by hexokinase (HK), and converted to glucose-6-phosphate (G6P). Thereafter, G6P is metabolized through either the glycolysis pathway or the pentose phosphate pathway. In the pentose phosphate pathway, G6P is converted to ribose-5-phosphate (R5P), a precursor of nucleotide synthesis, while NADPH is produced as a by-product. In the glycolysis pathway, the final product, pyruvate, is converted to acetyl-CoA, and enters the Krebs cycle in the mitochondria. NADH is generated in the Krebs cycle and used for oxidative phosphorylation where ATPs are produced. On the other hand, citrate generated in the Krebs cycle is released into the cytoplasm where it is converted to acetyl-CoA and then malonyl-CoA. Acetyl-CoA and malonyl-CoA are used for fatty acid production by fatty acid synthase (FASN). Fatty acids are further metabolized to fatty acyl-CoA and used for membrane synthesis, formation of lipid droplets, and signaling lipid production. G6PD; G6P dehydrogenase, 6PG; 6-phosphogluconolactone, F6P; fructose-6-phosphate, F1,6BP; fructose-1,6-bisphosphate, PFK1; phosphofructokinase 1, TIGAR; TP53-induced glycolysis and apoptosis regulator, LDHA; lactate dehydrogenase A, PDH; pyruvate dehydrogenase, PDK; pyruvate dehydrogenase kinase, AIF; apoptosis-inducing factor, SCO2; synthesis of cytochrome c oxidase 2, ACC; acetyl-CoA carboxylase.
Figure 7
Figure 7
Target genes of HIF-1. HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. BNIP3; BCL-2/E1B-19 kDa interacting protein 3, BNIP3L; BNIP3-like.
Figure 8
Figure 8
Anti-apoptotic function of AKT. AKT prevents apoptosis by suppressing induction of PUMA and by inhibiting GSK3-dependent degradation of MCL-1. In addition, AKT promotes translocation of GLUT to cellular membrane and activation of HK. GSK3; glycogen synthase kinase 3.
Figure 9
Figure 9
Metabolism-mediated modification of pro-apoptotic proteins. BAD is phosphorylated by AKT, PKA, and JNK that are regulated by glycolysis and growth factor signaling. Phosphorylation of BAD results in suppression of the antiapoptotic functions of BAD. Moreover, phosphorylated BAD contributes to activation of glucokinase and PFK1, therefore enhancing the glycolysis pathway. Atypical cyclin-dependent kinase, CDK5, is activated by glycolysis. Active CDK5 phosphorylates and inhibits the BH3-only protein NOXA. The pentose phosphate pathway produces NADPH, which also controls redox state of cytochrome c and suppresses apoptosome formation and apoptosis. PKA; protein kinase A, JNK; c-Jun NH2-terminal kinase, CaMKII; calcium-calmodulin-dependent kinase II.
Figure 10
Figure 10
Caspase-2 is metabolically regulated. In a state of glucose abundance, CoA-activated CaMKII phosphorylates caspase-2, which creates a binding site for 14-3-3ζ and keeps caspase-2 inactive. In periods of low glycolytic flux, 14-3-3ζ is acetylated, which triggers release of this adaptor protein from caspase-2, allowing for PP1-mediated dephosphorylation of caspase-2. PP1 and PP2A also dephosphorylate and inactivate CaMKII. The dephosphorylated form of caspase-2 can then be recruited to the PIDDsome for activation.
Figure 11
Figure 11
Metabolic enzymes targeted by p53. p53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.
Figure 12
Figure 12
Signaling lipid pathways. Ceramide is synthesized by three pathways; the de novo pathway, the sphingomyelinase (SMase) pathway, and the salvage pathway (see detail in main text).
Figure 13
Figure 13
Pro-apoptotic function of ceramide. Ceramide induces MOMP through the regulation of BAX by direct binding and suppression of BCL-2 in a p53-dependent manner. Ceramide also promotes apoptosis through the regulation of PP2A, AKT, and PKC. However, the precise molecular mechanisms are unknown. PP2A; protein phosphatase 2A, PKC; protein kinase C, MOMP; mitochondrial outer membrane permeabilization.
Figure 14
Figure 14
Activation of caspase-2 by FASN inhibitors is mediated by the mTOR pathway. Upon FASN inhibition, the mTOR inhibitory protein REDD1 is induced and stimulates caspase-2 activation and apoptosis in FASN-sensitive ovarian cancer cells. On the other hand, in FASN-resistant ovarian cancer cells, REDD1 induction is impaired, but mTOR inhibitor treatment can substitute function of REDD1 and restore caspase-2-mediated sensitization of cells to apoptosis.
Figure 15
Figure 15
Regulation of FASN activity and expression by HER2. In HER2-positive cancer cells, HER2 overexpression increases FASN expression through the PI3K/AKT and MEK/ERK pathways. HER2 also directly phosphorylates and enhances the enzymatic activity of FASN. FASN in turn upregulates HER2 expression, thereby establishing an autoregulatory loop. HER2; human epidermal growth factor receptor 2, FASN; fatty acid synthase, ERK; extracellular-signal-regulated kinase 2.
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