Resistance to anoikis in transcoelomic shedding: the role of glycolytic enzymes

Figures

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  Figure 1:. EMT and resistance to anoikis. Normal epithelial and premalignant cells undergo programmed cell death via anoikis upon detachment from the extracellular matrix/ tumor microenviroment (TME). Cancer cells develop resistance to anoikis and are able to survive in the peritoneal cavity despite shedding from the ECM/basement membrane. Key drivers of resistance to anoikis include TGF-β, Hypoxia-inducible factor (HIF), Epidermal-growth factor Receptor (EGF-R), Src, low pH, lactate, integrin α, heat shock protein (HSP), cytokines and the presence of Cancer-associated fibroblasts (CAFs) and ascites in the peritoneal cavity (Adapted from [15]).

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  Figure 2:. Mechanisms of resistance to anoikis. Survival strategies used by extracellular matrix (ECM)-detached metastatic cancer cells and corresponding signaling pathways (Adapted from [20]).

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  Figure 3:. Regulation of glycolysis and TCA cycle by HIF. HIF-1 enhances aerobic glycolysis in the cytoplasm by which glucose is metabolized to lactate rather than converted to acetyl-CoA to undergo oxidative phosphorylation (OXPHOS) in mitochondria. HIF-1 stimulates the utilization of glutamine and fatty acids as alternative substrates for mitochondrial energy production. OXPHOS: oxidative phosphorylation, TCA cycle: tricarboxylic acid or Krebs cycle; ROS: reactive oxygen species, LDHA: lactate dehydrogenase A, IDH: Isocitrate dehydrogenase, FAD: Flavin adenine dinucleotide, FASN: fatty acid synthase, NAD: Nicotinamide adenine dinucleotide, PDH: pyruvate dehydrogenase; PDK1: pyruvate dehydrogenase kinase isozyme 1, PK-M2: pyruvate kinase muscle isozyme 2; PGK1: Phosphoglycerate kinase 1 HK1,2: Hexokinase-1,2 (Adapted from [39]).

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  Figure 4:. Reverse Warburg effect. Cancer associated fibroblasts (CAFs) form spheroids with cancer cells shed into the peritoneal cavity, forming “Metastatic Units” (MU). Autophagy of fibroblasts provides cancer cells with nutrients and macromolecular building blocks. CAFs support energy metabolism of cancer cells by supplying them with lactate and amino acids. Aerobic glycolysis in cancer cells is more efficient (mitochondrial oxidation: 32 molecules ATP/molecule Glucose; aerobic glycolysis: 4 molecules ATP/molecule Glucose) than anaerobic glycolysis (2 molecules ATP/ molecule Glucose). MU facilitate resistance of cancer cells to anoikis (12).

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  Figure 5:. PGK1 activity in glycolysis and regulation by acetylation. PGK1 function is regulated by acetylation at K323, which enhances PGK1 enzymatic activity, improves glycolytic metabolism and promotes tumor growth. K323 acetylation is regulated by PCAF and SIRT7, allowing stimulation or inhibition of PGK1 function. P300/CBP-associated factor (PCAF) is a transcriptional coactivator associated with p53 promoting acetylation of PGK1. Conversely, NAD-dependent deacetylase sirtuin 7 (SIRT7), a nuclear enzyme, suppressed DNA recombination. GAPDH: glyceraldehyde 3 phosphate dehydrogenase. PGK1: Phosphoglycerate kinase 1 (Adapted from [76]).

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  Figure 6:. Role of PGK1 as a transcription factor. PGK1 is translocated into the nucleus. PGK1 is phosphorylated by casein kinase 2α (CK2α) at S256 under control of EGF-R and ERK 1/2. Phosphorylated PGK1 binds to Cell Division Cycle 7-related protein kinase (CDC7) and converts ADP to ATP. PGK1 also releases ADP inhibition on CDC7, which promotes DNA replication, cellular proliferation and tumourigenesis (Adapted from [73]).