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.
Yaxuan Zhou  1 ,  Jiro Tashiro  2 ,  Shiori Kamatani  2 ,  Nanami Irie  1 ,  Akito Suzuki  2 ,  Takuro Ishikawa  3 ,  Katsuhiko Warita  4 ,  Zoltán N Oltvai  5 ,  Tomoko Warita  6
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: [email protected].
  • 5. Department of Pathology and Laboratory Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY, 14642, USA. Electronic address: [email protected].
  • 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.
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