Figure 8
From: Hyperosmotic stress enhances cytotoxicity of SMAC mimetics
Hypertonicity boosts cytotoxicity of SMAC mimetics. Left side: SM trigger degradation of cIAP and thereby abolishes ubiquitination and subsequent proteasomal degradation of NIK. Increase in NIK levels results in non-canonical activation of the NFκB pathway and transcription of target genes such as TNF. In the absence of cIAP1/2, autocrine TNF secretion induces cell death via TNFR1. Right side: Under hypertonic conditions, SM also deplete cIAP1/2 and enable non-canonical NFκB activation, TNF release and TNFR1-induced cell death. Additionally, establishing an osmotic pressure gradient activates NFAT5, a vitally important transcription factor for a cell’s adaptive response to hyperosmotic stress. NFAT5 also triggers TNF transcription, which may restore SM cytotoxicity in cancer cells lacking autocrine SM-induced TNF production. RSC, receptor signaling complex
