Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat

Stefania Elena Navone, Laura Guarnaccia, Massimiliano D. Rizzaro, Laura Begani, Emanuela Barilla, Giovanni Alotta, Emanuele Garzia, Manuela Caroli, Antonella Ampollini, Aniello Violetti, Noreen Gervasi, Rolando Campanella, Laura Riboni, Marco Locatelli, Giovanni Marfia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.

Original languageEnglish
Article number130
JournalInternational Journal of Molecular Sciences
Volume25
Issue number1
DOIs
StatePublished - Jan 2024
Externally publishedYes

Keywords

  • ceramide
  • glioblastoma stem cells
  • glioma stem cells
  • luteolin
  • sphingolipid rheostat
  • sphingosine-1-phosphate
  • temozolomide

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