Siah2-GRP78 interaction regulates ROS and provides a proliferative advantage to Helicobacter pylori-infected gastric epithelial cancer cells.

Helicobacter pylori-mediated gastric carcinogenesis involves upregulation of the E3 ubiquitin ligase Siah2 and its phosphorylation-mediated stabilization. This study elucidates a novel mechanism of oxidative stress regulation by phosphorylated Siah2 in H. pylori-infected gastric epithelial cancer cells (GECs). We identify that H. pylori-mediated Siah2 phosphorylation at the 6th serine residue (P-S6-Siah2) enhances proteasomal degradation of the 78-kDa glucose-regulated protein (GRP78) possessing antioxidant functions. S6 phosphorylation stabilizes Siah2 and P-S6-Siah2 potentiates H. pylori-mediated reactive oxygen species (ROS) generation. However, infected S6A phospho-null Siah2-expressing cells have decreased cellular GRP78 level as surprisingly these cells release GRP78 to a higher extent and accumulate significantly higher ROS than the wild type (WT) Siah2 construct-expressing cells. Ectopic expression of GRP78 prevents the loss of mitochondrial membrane potential and cellular ROS accumulation caused by H. pylori. H. pylori-induced mitochondrial damage and mitochondrial membrane potential loss are potentiated in Siah2-overexpressing cells but these effects are further enhanced in S6A-expressing cells. This study also confirms that while phosphorylation-mediated Siah2 stabilization optimally upregulates aggresome accumulation, it suppresses autophagosome formation, thus decreasing the dependency on the latter mechanism in regulating cellular protein abundance. Disruption of the phospho-Siah2-mediated aggresome formation impairs proliferation of infected GECs. Thus, Siah2 phosphorylation has diagnostic and therapeutic significance in H. pylori-mediated gastric cancer (GC).

Hypoxia-driven metabolic heterogeneity and immune evasive behaviour of gastrointestinal cancers: Elements of a recipe for disaster.

Gastrointestinal (GI) cancers refer to a group of malignancies associated with the GI tract (GIT). Like other solid tumors, hypoxic regions consistently feature inside the GI tumor microenvironment (TME) and contribute towards metabolic reprogramming of tumor-resident cells by modulating hypoxia-induced factors. We highlight here how the metabolic crosstalk between cancer cells and immune cells generate immunosuppressive environment inside hypoxic tumors. Given the fluctuating nature of tumor hypoxia, the metabolic fluxes between immune cells and cancer cells change dynamically. These changes alter cellular phenotypes and functions, resulting in the acceleration of cancer progression. These evolved properties of hypoxic tumors make metabolism-targeting monotherapy approaches or immunotherapy-measures unsuccessful. The current review highlights the advantages of combined immunometabolic treatment strategies to target hypoxic GI cancers and also identifies research areas to develop better combinational therapeutics for future.

Silent hypoxia in COVID-19: a gut microbiota connection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has triggered the COVID-19 pandemic. Several factors induce hypoxia in COVID-19. Despite being hypoxic, some SARS-CoV-2-infected individuals do not experience any respiratory distress, a phenomenon termed 'silent (or happy) hypoxia'. Prolonged undetected hypoxia could be dangerous, sometimes leading to death. A few studies attempted to unravel what causes silent hypoxia, however, the exact mechanisms are still elusive. Here, we aim to understand how SARS-CoV-2 causes silent hypoxia.