Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming

Abstract

The attachment of cells to the extracellular matrix (ECM) is the hallmark of structure-function stability and well-being. ECM detachment in localized tumors precedes abnormal dissemination of tumor cells culminating in metastasis. Programmed cell death (PCD) is activated during tumorigenesis to clear off ECM-detached cells through "anoikis." However, cancer cells develop several mechanisms for abrogating anoikis, thus promoting their invasiveness and metastasis. Specific factors, such as growth proteins, pH, transcriptional signaling pathways, and oxidative stress, have been reported as drivers of anoikis resistance, thus enhancing cancer proliferation and metastasis. Recent studies highlighted the key contributions of metabolic pathways, enabling the cells to bypass anoikis. Therefore, understanding the mechanisms driving anoikis resistance could help to counteract tumor progression and prevent metastasis. This review elucidates the dynamics employed by cancer cells to impede anoikis, thus promoting proliferation, invasion, and metastasis. In addition, the authors have discussed other metabolic intermediates (especially amino acids and nucleotides) that are less explored, which could be crucial for anoikis resistance and metastasis.

Keywords: ECM detachment; anoikis; anoikis resistance; metabolism; tumor metastasis.

Figure 1

Mediators of anoikis-resistant cells. The figure depicts several factors altering anoikis mechanism, thus enhancing cancer cell survival following detachment, an important criterion for the initiation of metastasis cascade. ROS, reactive oxygen species. Image for anoikis resistant cells was adapted from (11).

Figure 2

Metabolic and signaling networks involved in anoikis-resistance mechanism. Several metabolic intermediates generate the energy required for cellular growth and survival; oncogenic activation of signaling pathways reprogram cellular metabolism to promote anoikis resistance. Metabolic pathways occur in different compartments, which involve the biosynthesis or degradation of biomolecules to supply energy needs of the cell. Glycolysis, PPP, protein, fatty acid, and nucleotide biosynthesis take place in the cytosol, while TCA and FAO occur in the mitochondria. The decarboxylation of pyruvate to acetyl-CoA takes place in the mitochondrial matrix. These metabolic pathways are interrelated with acetyl-CoA, which acts a key substrate for connecting these pathways. Metabolism is regulated by rate-limiting enzymes that allow the cell to maintain cellular homeostasis. However, the dysregulation of genes encoding these enzymes leads to metabolic perturbation that drives anoikis resistance preceding tumor metastasis. 6PGL, 6-Phosphogluconolactone; AMPK, Adenosine Monophosphate Kinase; ACC1, Acetyl Carboxylase 1; ATP, Adenosine Triphosphate; CSN, Citrate Synthase; EGFR, Epidermal Growth Factor Receptors; EMT, Epithelial-Mesenchymal Transition; ERK, Extracellular-Signal-Regulated Kinase; FAO, Fatty Acid Oxidation; FASN, Fatty Acid Synthase; FATP, Fatty Acid Transport Proteins; G3P, Glyceraldehyde-3-Phosphate; G6P, Glucose-6-Phosphate; G6PDH, Glucose-6-Phosphate Dehydrogenase; GLUT, Glucose Transporters; HIF, Hypoxia-Inducible Factors; HK, Hexokinase; IGFR, Insulin-Like Growth Factor-1 Receptor; LKB1, Liver Kinase B1; MAPK, Mitogen-Activated Protein Kinase; mTOR, Mammalian Target of Rapamycin; NF-κB, Nuclear Factor-Kappa B; PDH, Pyruvate Dehydrogenase; PEP, Phosphoenolpyruvate; PI3K, Phosphatidylinositol 3-Kinase; PPP, Pentose Phosphate Pathway; PTEN, Phosphatase and Tensin; ROS, Reactive Oxygen Species; STAT3, Signal Transducer and Activator of Transcription 3; TCA, Tricarboxylic Acid; TGF-β, Transforming Growth Factor-Beta; VLCFA, Very Long-Chain Fatty Acid.