Cholesterol sensor SCAP contributes to sorafenib resistance by regulating autophagy in hepatocellular carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted. Methods We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice. Results Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo. Conclusions SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma

“…In this study, CSCs were linked to a survival advantage over non-CSCs after sorafenib treatment of tumor cells, resulting in a significant increase in the relative proportion of CSCs in all HCC cell lines tested, and this may be related to liver cancer recurrence after sorafenib treatment ( Xin et al, 2013 ). In addition, Mok et al (2022) showed that SREBP2-mediated cholesterol biosynthesis is crucial for the increase of hepatic CSCs, and deletion of sterol-regulatory element binding protein 2 (SREBP2) and its chaperone SCAP conferred sensitivity to tyrosine kinase inhibitors in tumor-bearing mice ( Li et al, 2022 ; Mok et al, 2022 ).…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…In cases where autophagy inhibition is harmful, the induction of autophagy is beneficial for TKI therapy. 352 Serine and arginine-rich splicing factor 1 (SRSF1) is an autophagy suppressor, and its knockdown may activate autophagy and inhibit the proliferation of gefitinib-resistant cancer cells. 353 Cannabidiol promotes mitochondrial autophagy in CML cells by activating transient receptor potential vanilloid type 2 (TRPV2).…”

Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective

“…In a recent study, SCAP was shown to be substantially expressed in HCC tissues and associated with sorafenib resistance. Lycorine, a specific SCAP inhibitor, triggered autophagy by elevating AMPK activity, increasing the HCC cells’ sensitivity to sorafenib [ 135 ].…”