HMG-CoA reductase degrader, SR-12813, counteracts statin-induced upregulation of HMG-CoA reductase and augments the anticancer effect of atorvastatin

• Published in: Biochemical and biophysical research communications Vol. 677; pp. 13 - 19
• Main Authors: Zhou, Yaxuan, Tashiro, Jiro, Kamatani, Shiori, Irie, Nanami, Suzuki, Akito, Ishikawa, Takuro, Warita, Katsuhiko, Oltvai, Zoltán N., Warita, Tomoko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2023
• Subjects: Cancer cell; Dual inhibition; HMGCR; SR-12813; Statin; Targeted protein degradation; GGPP; Targeted protein degradation; Cancer cell; SREBP2; 25HC; TPD; Statin; HMGCR; EMT; Dual inhibition; SR-12813
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.07.056

Statins are cholesterol-lowering drugs that have exhibited potential as cancer therapeutic agents. However, as some cancer cells are resistant to statins, broadening an anticancer spectrum of statins is desirable. The upregulated expression of the statin target enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), in statin-treated cancer cells is a well-known mechanism of statin resistance, which can be counteracted by the downregulation of HMGCR gene expression, or degradation of the HMGCR protein. However, the mechanism by which HMGCR degradation influences the anticancer effects of statins remain unreported. We tested the effect of the HMGCR degrader compound SR-12813 at a concentration that did not affect the growth of eight diverse tumor cell lines. Combined treatment with atorvastatin and a low concentration of SR-12813 led to lowering of increased HMGCR expression, and augmented the cytostatic effect of atorvastatin in both statin-resistant and -sensitive cancer cells compared with that of atorvastatin treatment alone. Dual-targeting of HMGCR using statins and SR-12813 (or similar compounds) could provide an improved anticancer therapeutic approach. •Atorvastatin and SR-12813 co-treatment augmented the cytostatic effects of statins.•The cytostatic effect of statin and SR-12813 co-treatment was specific to HMGCR.•Dual targeting of HMGCR by statins and SR-12813 may improve antitumor therapy.