Cancer cells in the inner region of avascularized solid tumours experience metabolical stress by hypoxic and
glucose depletion (OGD) and are prone to die by
necrosis to form a necrotic core, a common feature of solid tumours. Unlike in apoptosis, where the cellular contents remain packed in the apoptotic bodies that are removed by macrophages,
necrosis is characterized by cell membrane
rupture, and the release of many cellular
proteins including tumour promoting
cytokine high mobility group box 1 (
HMGB1) into the extra-cellular space. Although ROS produced by metabolic stress are known to cause membrane damage leading to the plasma membrane
rupture, its molecular mechanism remains unclear. In this study, we show that some cellular
proteins including pro-apoptotic molecules p53,
caspase-3, and
caspase-9 and a pro-autophagic molecule
beclin 1 are not released into the extracellular space but rather aggregated in the cytosol during GD-induced
necrosis and that the
protein aggregation occurs in a ROS-dependent manner. We also found that Snail, the
transcription factor that is induced by GD, was not translocated to the nucleus and aggregated in the cytosol. In addition, Snail interference appeared to block metabolic stress-induced
protein aggregation, indicating a critical role(s) of Snail in the
protein aggregation. These results demonstrate that in metabolically stressed
cancer cells, ROS induce a specific set of cellular
proteins to form insoluble aggregates that are highly toxic to cells and trigger the
necrosis-associated membrane
rupture and
HMGB1 release to promote tumour progression.