Modulating voltage-gated sodium channels to enhance differentiation and sensitize glioblastoma cells to chemotherapy.

Autor: Giammello F; Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, 27100, Italy.; PhD Program in Genetics, Molecular and Cellular Biology, University of Pavia, Pavia, Italy., Biella C; IRCCS San Raffaele Hospital, Via Olgettina 58, Milan, 20132, Italy., Priori EC; Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, 27100, Italy., Filippo MADS; Department of Biosciences, University of Milan, Milan, 20133, Italy., Leone R; Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, 27100, Italy., D'Ambrosio F; Department of Biosciences, University of Milan, Milan, 20133, Italy., Paterno' M; Department of Biosciences, University of Milan, Milan, 20133, Italy., Cassioli G; Department of Biosciences, University of Milan, Milan, 20133, Italy., Minetti A; CNR Neuroscience Institute of Pisa, Via Giuseppe Moruzzi, 1, Pisa (PI), 56124, Italy., Macchi F; CNR Neuroscience Institute of Pisa, Via Giuseppe Moruzzi, 1, Pisa (PI), 56124, Italy., Spalletti C; CNR Neuroscience Institute of Pisa, Via Giuseppe Moruzzi, 1, Pisa (PI), 56124, Italy., Morella I; Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, 27100, Italy., Ruberti C; Advanced Technology Platform, Department of Biosciences, University of Milan, Milan, 20133, Italy., Tremonti B; Pharmacology Unit, Department of Internal Medicine, University of Genova, Genova, 16132, Italy., Barbieri F; Pharmacology Unit, Department of Internal Medicine, University of Genova, Genova, 16132, Italy., Lombardi G; Department of Oncology 1, Oncology, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata 64, Padua, 35128, Italy., Brambilla R; Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, 27100, Italy., Florio T; Pharmacology Unit, Department of Internal Medicine, University of Genova, Genova, 16132, Italy.; IRCCS Ospedale Policlinico San Martino, Genova, 16132, Italy., Galli R; IRCCS San Raffaele Hospital, Via Olgettina 58, Milan, 20132, Italy., Rossi P; Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, 27100, Italy., Brandalise F; Department of Biosciences, University of Milan, Milan, 20133, Italy. federico.brandalise@unimi.it.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Sep 09; Vol. 22 (1), pp. 434. Date of Electronic Publication: 2024 Sep 09.
DOI: 10.1186/s12964-024-01819-z
Abstrakt: Background: Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle.
Methods: We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Na v ) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Na v activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Na v in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo.
Results: We demonstrated that Na v is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Na v made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Na v substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Na v positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Na v .
Conclusions: This insight positions Na v as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment.
(© 2024. The Author(s).)
Databáze: MEDLINE
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