Dual roles of β-arrestin 1 in mediating cell metabolism and proliferation in gastric cancer

β-Arrestin 1 (ARRB1) has been recognized as a multifunctional adaptor protein in the last decade, beyond its original role in desensitizing G protein-coupled receptor signaling. Here, we identify that ARRB1 plays essential roles in mediating gastric cancer (GC) cell metabolism and proliferation, by combining cohort analysis and functional investigation using patient-derived preclinical models. Overexpression of ARRB1 was associated with poor outcome of GC patients and knockdown of ARRB1 impaired cell proliferation both ex vivo and in vivo. Intriguingly, ARRB1 depicted diverse subcellular localizations during a passage of organoid cultures (7 d) to exert dual functions. Further analysis revealed that nuclear ARRB1 binds with transcription factor E2F1 triggering up-regulation of proliferative genes, while cytoplasmic ARRB1 modulates metabolic flux by binding with the pyruvate kinase M2 isoform (PKM2) and hindering PKM2 tetramerization, which reduces pyruvate kinase activity and leads to cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis. As ARRB1 localization was shown mostly in the cytoplasm in human GC samples, therapeutic potential of the ARRB1-PKM2 axis was tested, and we found tumor proliferation could be attenuated by the PKM2 activator DASA-58, especially in ARRB1high organoids. Together, the data in our study highlight a spatiotemporally dependent role of ARRB1 in mediating GC cell metabolism and proliferation and implies reactivating PKM2 may be a promising therapeutic strategy in a subset of GC patients.

 

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The passage you provided describes a study that explores the role of β-Arrestin 1 (ARRB1) in gastric cancer (GC) cell metabolism and proliferation. In recent years, ARRB1 has been found to have multiple functions beyond its original role in desensitizing G protein-coupled receptor signaling. The researchers used a combination of cohort analysis and patient-derived preclinical models to investigate the functions of ARRB1 in GC.

The study found that overexpression of ARRB1 was associated with poor outcomes in GC patients. Additionally, when ARRB1 was knocked down, it impaired cell proliferation both in laboratory experiments (ex vivo) and in live animal models (in vivo). Interestingly, during the passage of organoid cultures (a three-dimensional cell culture model), ARRB1 was found to have different subcellular localizations and exert dual functions.

Further analysis revealed that nuclear ARRB1 binds with a transcription factor called E2F1, which leads to the up-regulation of genes involved in cell proliferation. On the other hand, cytoplasmic ARRB1 interacts with an isoform of the pyruvate kinase enzyme called PKM2, hindering its tetramerization. This disruption of PKM2 activity reduces pyruvate kinase function, shifting cellular metabolism from oxidative phosphorylation to aerobic glycolysis.

The researchers observed that ARRB1 was mostly localized in the cytoplasm in human GC samples. Based on this finding, they tested the therapeutic potential of targeting the ARRB1-PKM2 axis. They found that tumor proliferation could be attenuated by using a PKM2 activator called DASA-58, especially in organoids with high levels of ARRB1 expression.

Overall, this study highlights the multifunctional role of ARRB1 in mediating GC cell metabolism and proliferation. It suggests that the spatiotemporal localization of ARRB1 determines its specific functions and provides insights into potential therapeutic strategies targeting the ARRB1-PKM2 axis in a subset of GC patients.