Figure 9.

Illustration of the likely apoptosis pathway in action following C1q binding to SKOV3 cells. Exogenous treatment of SKOV3 cells with C1q and individual globular head modules can induce upregulation of TNF-α and Fas. TNF-α stimulation triggers two parallel, but contrasting, pathways: the pro-apoptotic caspase (15) and the anti-apoptotic NFκB-IκB inhibitor of apoptosis proteins (IAP) pathway (16). The cell survival or death, however, depends upon interactions among the components of these two pathways as well as other factors such as mitochondrial dysfunction (15, 16). TNF-α can bind to TNF type I receptor (TNFR1), which is then internalized to first form a complex with TNFR1-associated DEATH domain, receptor-interacting protein 1 (RIP1), TNF receptor-associated factor 2 (TRAF2), and cellular inhibitor of apoptosis protein-1 (c-IAP1) (complex I), triggering the upregulation of nuclear factor-κB (NF-κB). A second complex (complex II) is later formed when complex I bind to Fas-associated protein with death domain (FADD), which is recruited upon activation of Fas (15, 17). Complex II subsequently causes downstream activation of apoptosis signal by activating caspase cascade, resulting in the cleavage of initiator caspase 8 and effector caspase 3 leading to apoptosis (15, 17–19). However, NF-κB upregulation may intersect apoptotic pathway as it can promote the induction of various cellular apoptosis inhibitors such as TRAF1, TRAF2, cIAP-1, c-IAP-2, and X-linked inhibitor of apoptosis protein (XIAP) (15, 20).