Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis Open Access

Boese, Austin (Summer 2023)

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Dysregulated cellular metabolism is a common characteristic of cancer, but recent studies highlight significant differences in metabolic phenotypes both within primary tumors, and in tumor cells that metastasize to distant organs. While highly proliferative primary tumor cells often exhibit the Warburg effect, marked by a preference for aerobic glycolysis to generate ATP, genes for mitochondrial biogenesis and oxidative phosphorylation are often upregulated in metastatic cancer cells. Therefore, detailed characterization of reprogrammed metabolic pathways in metastatic cancer may reveal useful targets to combat tumor progression and improve patient survival.

To successfully metastasize, cancer cells must first resist anoikis: an apoptotic cell death mechanism triggered by loss of proper contact with the extracellular matrix. Our lab has previously demonstrated that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) contributes to anoikis resistance and metastasis by regulating the bioenergetic response through reactivation of AMPK in LKB1-deficient lung cancer. However, the role of other mitochondrial enzymes in anoikis resistance remains poorly understood. To identify other factors important for cancer cell anoikis resistance, we performed an unbiased RNAi screen targeting 120 mitochondrial enzymes in lung cancer cells and identified the ATP-specific Succinyl-CoA Synthetase beta subunit (SUCLA2) as an important factor for cancer cell survival after ECM detachment. Stable knockdown of SUCLA2 sensitized several cancer cell lines to anoikis when cultured under non-adherent conditions in vitro. Bioinformatic analysis of publicly available data revealed that higher tumor SUCLA2 mRNA expression is associated with poor cancer patient overall survival, and immunohistochemistry staining indicated that SUCLA2 protein levels are higher in metastatic lung and breast cancer tumors compared to their matched primary tumors. Detailed metabolic assays showed that the metabolic contribution of SUCLA2 during metastasis is independent of its role in the Krebs cycle and involves promoting protein expression of redox scavenging enzymes through stress granules in the cytosol. These findings provide a framework to identify and characterize novel metabolic features that selectively promote metastasis of solid tumors. Collectively, these data expand our understanding of the molecular mechanisms that drive cancer metastasis and identify SUCLA2 as a promising target that should be studied further for future anti-metastatic cancer therapy.

Table of Contents

1. Background...1

1.1 Metabolic reprogramming is linked to cancer progression and metastasis...2

1.2 Reactive oxygen species are a double-edged sword in cancer...3

1.3 Glutaminolysis regulates redox in cancer...5

1.4 Some cancers restrict glucose oxidation to prevent oxidative stress...11

1.5 Cancer cells upregulate their antioxidant defense systems to combat oxidative stress...12

1.6 Detection and treatment of metastatic cancer remains a significant clinical challenge...16

1.7 In vitro screening identifies mitochondrial metabolic targets that promote anoikis resistance and cancer metastasis...18

2. Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis...19

2.1 Introduction...20

2.2 Materials and Methods...22

2.3 Results...28

3. General Discussion and Future Directions...48

4. Acknowledgements...50

5. References...51

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