Involvement of Protein Kinase C Delta and Monocarboxylate Transporter 4 in the Development of Statin-Induced Cytotoxicity in a Rhabdomyosarcoma-Derived Cell Line
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.
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BibTeX
@article{okamoto2026involvement,
title = {{Involvement of Protein Kinase C Delta and Monocarboxylate Transporter 4 in the Development of Statin-Induced Cytotoxicity in a Rhabdomyosarcoma-Derived Cell Line}},
author = {Keisuke Okamoto and Toya Matsui and Yurika Kikutani and Hinata Ueda and Ayako Furugen and Katsuya Narumi and Masaki Kobayashi},
journal = {Biological and Pharmaceutical Bulletin},
year = {2026},
month = sep,
doi = {10.1248/bpb.b25-00680},
url = {https://www.jstage.jst.go.jp/article/bpb/49/9/49_b25-00680/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Involvement of Protein Kinase C Delta and Monocarboxylate Transporter 4 in the Development of Statin-Induced Cytotoxicity in a Rhabdomyosarcoma-Derived Cell Line
AU - Keisuke Okamoto
AU - Toya Matsui
AU - Yurika Kikutani
AU - Hinata Ueda
AU - Ayako Furugen
AU - Katsuya Narumi
AU - Masaki Kobayashi
PY - 2026
DA - 2026/09/05
JO - Biological and Pharmaceutical Bulletin
DO - 10.1248/bpb.b25-00680
UR - https://www.jstage.jst.go.jp/article/bpb/49/9/49_b25-00680/_article
AB - 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.
SN - 1347-5215
SN - 0918-6158
ER -