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

Yaxuan Zhou; Jiro Tashiro; Shiori Kamatani; Nanami Irie; Akito Suzuki; Takuro Ishikawa; Katsuhiko Warita; Zoltán N Oltvai; Tomoko Warita

doi:10.1016/j.bbrc.2023.07.056

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

Biochem Biophys Res Commun. 2023 Oct 15:677:13-19. doi: 10.1016/j.bbrc.2023.07.056. Epub 2023 Jul 27.

Authors

Yaxuan Zhou¹, Jiro Tashiro², Shiori Kamatani², Nanami Irie¹, Akito Suzuki², Takuro Ishikawa³, Katsuhiko Warita⁴, Zoltán N Oltvai⁵, Tomoko Warita⁶

Affiliations

¹ Graduate School of Science and Technology, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1330, Japan.
² Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, Tottori, 680-8553, Japan.
³ Department of Anatomy, School of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
⁴ Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori, Tottori, 680-8553, Japan. Electronic address: waritak@tottori-u.ac.jp.
⁵ Department of Pathology and Laboratory Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY, 14642, USA. Electronic address: Zoltan_Oltvai@URMC.Rochester.edu.
⁶ Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, Hyogo, 669-1330, Japan.

PMID: 37541087
DOI: 10.1016/j.bbrc.2023.07.056

Abstract

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.

Keywords: Cancer cell; Dual inhibition; HMGCR; SR-12813; Statin; Targeted protein degradation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Atorvastatin / pharmacology
Hydroxymethylglutaryl CoA Reductases / genetics
Hydroxymethylglutaryl CoA Reductases / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
Up-Regulation

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Atorvastatin
3-hydroxy-3-methylglutaryl-coenzyme A
SR 12813
Hydroxymethylglutaryl CoA Reductases