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

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-12, Vol.25 (1), p.130
Main Authors: Navone, Stefania Elena, Guarnaccia, Laura, Rizzaro, Massimiliano D, Begani, Laura, Barilla, Emanuela, Alotta, Giovanni, Garzia, Emanuele, Caroli, Manuela, Ampollini, Antonella, Violetti, Aniello, Gervasi, Noreen, Campanella, Rolando, Riboni, Laura, Locatelli, Marco, Marfia, Giovanni
Format: Article
Language:English
Subjects:
Apoptosis
Autophagy
Bioflavonoids
Brain cancer
Brain tumors
Cancer therapies
Care and treatment
Cell culture
Cell cycle
ceramide
Chemotherapy
Development and progression
Flavones
Flavonoids
Glioblastoma multiforme
glioblastoma stem cells
Glioma
Health aspects
Kinases
Lipids
luteolin
Patients
Phosphates
Radiation therapy
sphingolipid rheostat
Sphingosine
sphingosine-1-phosphate
Stem cells
temozolomide
Transplantation
Tumor proteins
Tumors
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25010130