Abstract
Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.
Highlights
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, and it is characterized by an aggressive clinical course
We examined the pharmacokinetics of Betulinic acid (BA) in U87MG, A172, P3, and P5 cells at different concentrations (20 and 40 μM) for 2 days
Results revealed that BA acted in a concentration-dependent manner to suppress the rate of proliferation in all GBM cell lines and corresponding TMZ-resistant cells (Figure 1A)
Summary
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, and it is characterized by an aggressive clinical course. Previous studies revealed that the ER chaperone glucose-regulated protein 78 (Grp, known as BiP) serves as a master regulator of ER stress and plays important roles in activating three major signaling events, initiated by inositol-requiring enzyme-1 (IRE1α), activating transcription factor 6. ER stress-related factors may have roles contributing to tumorigenesis and to the development of TMZ resistance in GBM. Altering the activities of these factors may be a potential strategy to overcome brain-tumor recurrence after initial therapy. Our previous study showed that BA affected the SUMOylation of the oncogenic specificity protein 1 (Sp1) transcription factor, thereby inhibiting lung-cancer growth [13]. In this study, we evaluated the applicability of BA as a potential therapeutic agent for the treatment of GBM, in TMZ-resistant and recurrent GBM, through inhibition of ER stress tolerance
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