Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization

Silvia Codenotti; Michela Asperti; Maura Poli; Luisa Lorenzi; Alberto Pietrantoni; Matteo Cassandri; Francesco Marampon; Alessandro Fanzani

doi:10.1016/j.molmet.2024.102085

Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization

Mol Metab. 2024 Dec 18:102085. doi: 10.1016/j.molmet.2024.102085. Online ahead of print.

Authors

Silvia Codenotti¹, Michela Asperti², Maura Poli², Luisa Lorenzi³, Alberto Pietrantoni³, Matteo Cassandri⁴, Francesco Marampon⁵, Alessandro Fanzani⁶

Affiliations

¹ Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. Electronic address: silvia.codenotti@unibs.it.
² Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
³ Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; ASST Spedali Civili di Brescia, 25123, Brescia, Italy.
⁴ Department of Radiological Sciences, Oncology and Anatomic Pathology, "Sapienza" University of Rome, 00161, Rome, Italy.
⁵ Department of Pediatrics, "Sapienza" University of Rome, Rome, Italy.
⁶ Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. Electronic address: alessandro.fanzani@unibs.it.

PMID: 39706565
DOI: 10.1016/j.molmet.2024.102085

Abstract

By analyzing RNA datasets from rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people, we found upregulation of sterol regulatory element-binding protein 2 (SREBP2) and mevalonate pathway (MVP) genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival and predicted statin sensitivity. In human RD and RH30 lines, treatment with 0.01-1 μM doses of fatostatin (SREBP2 inhibitor), lovastatin and simvastatin (HMGCR inhibitors), and zoledronic acid (FDPS inhibitor) impaired cell growth and migration, which were conversely stimulated by 50-100 μM cholesterol (CHO) supplementation. Treatment of RMS lines with higher doses of SREBP2 and MVP inhibitors (5-50 μM) promoted oxidative cell death and chemosensitization in combination with actinomycin D. Administration of lovastatin or fatostatin to RD and RH30 cells produced a rapid attenuation of Erk1/2 and Akt1 phosphorylation, detectable after 4 h of treatment. Furthermore, tumor mass growth of xenografted RD cells in NOD/SCID mice was reduced by oral administration of lovastatin. Lastly, we found the forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression and enhance cell death susceptibility to MVP inhibitors. Taken together, these data suggest that the axis formed by Akt1, SREBP2 and MVP is critical for RMS tumor growth, migration, and oxidative stress protection mainly through the maintenance of CHO levels that ensure proper intracellular signaling. Therefore, targeting CHO levels by SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol in RMS.

Keywords: Chemoresistance; Cholesterol; Mevalonate pathway; Oxidative stress; Rhabdomyosarcoma.