Authors
Keisuke Okamoto, Toya Matsui, Yurika Kikutani, Hinata Ueda, Ayako Furugen, Katsuya Narumi, Masaki Kobayashi
Published in
Biological & pharmaceutical bulletin. Volume 49. Issue 9. Pages 1438-1443.
Abstract
Statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, are widely prescribed lipid-lowering agents. Nevertheless, their use is occasionally associated with muscle toxicity, including rhabdomyolysis. Exercise reportedly exacerbates statin-induced muscle injury; however, the underlying mechanisms remain poorly understood. Here, we investigated the role of protein kinase C (PKC) signaling in the development of statin-induced cytotoxicity using a rhabdomyosarcoma-derived cell line (RD cells), with particular emphasis placed on the regulation of monocarboxylate transporter 4 (MCT4), a lactate transporter implicated in intracellular acidification and cytotoxic responses. Treatment with simvastatin, atorvastatin, and fluvastatin reduced RD cell viability in a concentration-dependent manner. Co-treatment with bisindolylmaleimide I (BIM), an inhibitor of PKCα, β, γ, δ, and ε, attenuated statin-induced cytotoxicity and tended to suppress simvastatin-induced MCT4 upregulation. Furthermore, co-treatment with Gö6976, a selective inhibitor of PKCα and β, did not mitigate the simvastatin-induced reduction in cell viability. Small interfering RNA-mediated knockdown of PKCδ significantly rescued simvastatin-induced cytotoxicity. Tamoxifen, a clinically available drug with PKC inhibitory activity, including against the δ isoform, attenuated simvastatin-induced cell injury, paralleling the effects of BIM. Collectively, our findings demonstrate that PKCδ contributes to statin-induced cytotoxicity in rhabdomyosarcoma cells, at least in part by regulating MCT4 expression.
PMID:
42702544
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.
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