Fig. 7.

Scheme of potential mechanisms of SKO induced necrosis and apoptosis in MDA-MB-231 cells. a In steady-state condition, cIPAs facilitates trans-ubiquitination of NF-κB-inducing kinase (NIK) and degraded by proteasome. Meanwhile, cIPAs play as E3 like ubiquitination enzyme to continuously ubiquitination of RIP1 to promote cell survival. When stimulated by SKO, cIPAs enter into auto-ubiquitination process and degraded by proteasome, which triggers the activation of NIK-TNF signaling to promote the autocrine of TNF in the culture medium. The activity of proteasome is inhibited by proteasome inhibitor LAC. b Over accumulation of autocrine TNF binds to the receptor of TNF-R1, and further triggers the TNF induced apoptotic and necrotic signaling pathways. Inhibition the activity of RIP1 by adding Nec-1 successfully rescue cells from SKO induced apoptosis and necrosis