Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy

• DOI: 10.1007/s12072-014-9582-0
• Publication Date: 2014-09-30T14:50:41Z
• Authors: Yves-Paul Vandewy...; Debby Laukens; Eliene Bogaerts; Annelies Paridaens; Anja Van den Bussche; Xavier Verhelst; Christophe Van St...; Benedicte Descamps; Chris Vanhove; Louis Libbrecht; Riet De Rycke; Bart N. Lambrecht; Anja Geerts; Sophie Janssens; Hans Van Vlierberghe
• Keywords: ATF6

Abstract Background Functional disturbances of the endoplasmic reticulum (ER) lead to activation unfolded protein response (UPR), which is involved in consecutive steps carcinogenesis. In human hepatocellular carcinoma (HCC), UPR shown be activated; however, little known about kinetics and effects modulation HCC. Methods We sequentially monitored over time an orthotopic mouse model for HCC explored on cell viability proliferation vitro model. Results The expression ER-resident chaperones peaked during tumor initiation increased further progression, predominantly within nodules. A peak Ire1 signaling was observed initiation. Perk pathway activated proapoptotic target Chop upregulated from week 5 continued rise, especially tumors. Atf6 modestly only after Consistent with activation, electron microscopy demonstrated ER expansion reorganization cells vivo. Strikingly, under stress or hypoxia, inhibitor not reduced via escalating proteotoxic vitro. Notably, significantly decreased burden Conclusion provide first evaluation dynamics a long-term cancer identified small molecule as promising strategy therapy.