Fig 9. Schematic representation of possible HFCP-induced cell death mechanisms in HepG2 and A549 cells.

Proteins from cells exposed to HFCP undergo ubiquitination, leading to their aggregation. The formation of p62-caspase-8 aggregates would lead to caspase-8 cleavage and its activation. Active caspase-8 induces PARP and ubiquitinates cleaved active caspase-3. The accumulation of protein aggregates also triggers autophagy, which could also trigger caspase-8 activation. However, none of these pathways appears to play a role in inducing HepG2 cell death. In contrast, Z-VAD-fmk is partly protective toward HFCP-induced cell death in A549 cells, indicating that apoptosis may participate in cell death. Furthermore, 3-MA further increases cell death, indicating that autophagy may be protective. Other alternative yet unknown mechanisms may also be involved under these conditions.