https://orcid.org/0000-0003-2797-6153
Figures & data
Figure 1 Mechanism of HIF-dependent sorafenib sensitization. HIFα is hydroxylated by prolyl hydroxylases under normoxia conditions and binds with VHL. Following ubiquitination by VHL, HIFα is degraded by 26S proteosomes. HIFα can be packaged by autophagosomes and transported to lysosomes for hydrolysis. ICI118.511 can inhibit autophagy-dependent HIF degradation by inhibiting ADRB2. HIFα can be translocated to the nucleus where it functions as a transcription factor. This process is pharmacologically inhibited by EF24. HIF translocation is also dependent on MAPKs located in the cytosol. LB100 inhibits HIF function through MAPK inhibition. Meloxicam and celecoxib can also inhibit MAPK through the COX-PGF2 axis, thereby inhibiting HIF translocation and function. HIFs transcriptionally activate multiple genes, including Bcl-2 and p21/p27, which mediate cell apoptosis, PKM2 and GLUT1, induce metabolic reprogramming and shift cell energy metabolism to aerobic glycolysis. Simvastatin inhibits PKM2 and sensitizes HCC cells to sorafenib. HIFs also regulate cell proliferation and angiogenesis by upregulating IGF and VEGF levels.
