Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

Abstract

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.

Keywords: Bcl2 family protein; Warburg effect; ceramide metabolism; glycolysis; mitophagy; non-small cell lung carcinoma.

Figure 1

Autophagy is a self-eating mechanism occurring in cells. (A) Different steps in the autophagy pathway. Cargos are first engulfed by autophagosomes, which then fuse with lysosomes. Lysosomal enzymes degrade the cargo resulting in the recycling of the cargo’s building blocks. (B) Selective autophagy. Autophagy can selectively target and degrade specific cargo using different receptor proteins.

Figure 2

(A) Glycolysis: This includes 10 consecutive enzymatic reactions in the conversion of glucose into two molecules of pyruvate, which connect with other metabolic pathways. Glucose is phosphorylated to glucose 6-phosphate by the enzyme hexokinase (HK). Glucose 6-phosphate is turned into fructose 6-phosphate by glucose phosphate isomerase (GPI). Phosphofructokinase-1 (PFK) catalyzes the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. 6-phosphofructo2-kinase/fructose 2,6-bisphosphatase (PFKFB), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (PFKFB3 and PFKFB4 are the two main isoenzymes of this family) (PFK and PFKFB are the two major regulatory enzymes in glycolysis). Subsequently, the aldolase enzyme catalyzes a reversible reaction in which fructose 1,6-bisphosphate converts into glyceraldehyde-3-phosphate (GLAP) and dihydroxyacetone phosphate (DHAP). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) produces 1,3-bisphosphoglycerate. Next, phosphoglycerate kinase (PGK) forms ATP and 3-phosphoglycerate. Phosphoglycerate mutase (PGM) isomerizes 3-phosphoglycerate into 2-phosphoglycerate. Next, enolase converts 2-phosphoglycerate to phosphoenolpyruvate, which is phosphorylated to form a molecule of pyruvate and a molecule of ATP via pyruvate kinase (PK). Finally, lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate. (B) Krebs cycle: The TCA cycle starts with the combination of acetyl-CoA, generated from fatty acids, amino acids, or pyruvate oxidation, with oxaloacetate (OAA) to produce citrate. Citrate is converted into isocitrate. The cycle continues with two consecutive oxidative decarboxylations in which isocitrate is converted into the α-ketoglutarate (α-KG) and the succinyl-CoA concomitantly, producing two CO₂ and two NADH. Succinyl-CoA coverts into succinate, coupled with the release of ATP. Subsequently, fumarate is formed by the oxidation of succinate. During this step, two hydrogen atoms are transferred to FAD, producing 2FADH. Next, fumarate is converted into malate and further into OAA, which combines with another acetyl-CoA, continuing the cycle [51]. (C) De novo lipogenesis C: In this simplified scheme, pyruvate from glycolysis feeds acetyl-CoA to the TCA cycle. Citrate from the TCA cycle is converted to acetyl-CoA in the cytosol by ATP citrate lyase (ACLY). Acetyl-CoA from the TCA cycle and other sources is subsequently converted to complicated fatty acids by a series of enzymes including ATP-citrate lyase (ACLY), acetyl-CoA carboxylases 1 (ACC1), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1). (D) Fatty acid β-oxidation: Each cycle leads to the formation of acetyl-CoA, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FADH 2). The electron carriers NADH and FADH2 are used by the mitochondrial respiratory chain to generate ATP. (E) Triacylglycerol synthesis: This reaction occurs at the surface of the endoplasmic reticulum (ER) bilayer membrane. The first step in this pathway is the acylation of glycerol-3-phosphate by glycerol-3-phosphate acyltransferase (GPAT), producing lysophosphatidic acid. This is followed by further acylation by LPA acyltransferase (LPAAT) and dephosphorylation by phosphatidic acid phosphorylase (PAP) to yield diacylglycerol (DAG). The final step is converting 1,2-diacylglycerol into triacylglycerol (TAG), which is catalyzed by diacylglycerol acyltransferase (DGAT).

Figure 3

Autophagy is regulated by multiple signaling pathways, which creates a complex interaction system. The glycolysis-related enzymes and glycolysis metabolic intermediates (A–F) are involved in the regulation of autophagy, acting as a double-edged sword to sustain cancer cell survival under conditions of energy shortage.

Figure 4

Hypoxia-induced autophagy (left): Hypoxic stress leads to the accumulation of HIF-1a. BNIP3 and BNIP3L, gene products targeted by HIF, are transcriptionally upregulated and compete with the Bcl-XL and Bcl-2 complex. This competition releases BECLIN1 from the complex, leading to the activation of autophagic machinery through the recruitment of several autophagic proteins including ATG5 and LC3. Acid-induced autophagy (right): Upon MCT1-mediated entry, lactate and NAD+ are converted into pyruvate, NADH, and H+ by LDHB. Then, the protons generated by LDHB can promote lysosomal acidification and autophagy.

Figure 5

Crosstalk between lipids and autophagy. Lipids can modulate autophagy through different mechanisms.

Figure 6

Mechanism of action of autophagy regulation upon HMGCR inhibition by statins. In addition, the mechanism by which FASN can modulate autophagy during cancer is shown. ACLY: ATP citrate lyase; ACAT: acetyl-CoA acetyltransferase; HMGCS: 3-hydroxy-3-methylglutaryl-CoA synthase; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; ACC: acetyl-CoA carboxylase; FASN: fatty acid synthase; SCD: stearoyl-CoA desaturase; MUFA: monounsaturated fatty acid; PUFA: polyunsaturated fatty acid.

Figure 7

SPHK1 and FAT can regulate autophagy during cancer. A simplified scheme of sphingolipid metabolism and turnover is also shown.

Figure 8

(A): Overall Survival Kaplan–Meier Estimate of LUAD cancer patients with BCL2L1 gene amplification (red) or without (blue). (B): Disease/Progression-free Kaplan–Meier Estimate in LUAD cancer patients with BCL2L1 gene amplification (red) and without (blue). Graph from Oncomine.org site using TCGA cancer data [327,328,329].

Figure 9

Schematic representation highlighting the metabolic pathways upregulated in cancer. In tumour cells, the uptake of glucose and aerobic glycolysis (the Warburg effect) are upregulated for rapid ATP production. The abundance of lactate that is produced is excreted into the extracellular space/tumour microenvironment. Some pyruvate is shunted into the mitochondrion for OXPHOS. The excess glucose feeds into biosynthesis, such as nucleotide, protein, and lipid synthesis, which supports uncontrolled proliferation. Altered glucose metabolism is linked to altered lipid metabolism in tumour cells, as glucose is the major substrate for lipid synthesis. Both endogenous fatty acid synthesis and fatty acid uptake are upregulated in tumour cells. The fatty acids can be subsequently used for ATP production through β-oxidation, which is also upregulated in tumour cells and supports uncontrolled growth and proliferation. ATP, adenosine triphosphate; CPT1, carnitine palmitoyl transferase 1; ETC, electron transport chain; FAO, fatty acid oxidation; FAS, fatty acid synthesis; GLUT, glucose transporter; MCT4, monocarboxylate transporter 4; PPP, pentose phosphate pathway; TCA cycle, tricarboxylic acid cycle.