Abstract
Background:Up-regulation of PIK3R3 (Phosphoinositide-3-Kinase Regulatory Subunit 3), the regulatory subunit of PI3K is correlated with the drug resistance of the glioblastoma cells. In the present study, the effect of PIK3R3 siRNA on erlotinib sensitivity of the U373-MG glioblastoma cells was explored. Methods:After PIK3R3 siRNA transfection, the expression of PIK3R3 mRNA was measured using RT-qPCR. Trypan blue exclusion assay was used to explore the effect of PIK3R3 siRNA on cell proliferation. The effects of PIK3R3 siRNA and erlotinib, alone and in combination, on cell survival and apoptosis were measured using MTT assay and ELISA cell death assay, respectively. Results:Our data showed that PIK3R3 siRNA markedly suppressed the expression of PIK3R3 in a time dependent way, inhibited the proliferation of the U373-MG cells and triggered apoptosis (p <0.05, relative to blank control). Pretreatment with PIK3R3 siRNA synergistically decreased the cell survival rate and lowered the IC50 of erlotinib. Moreover, PIK3R3 siRNA markedly enhanced the apoptotic effect of erlotinib. Conclusions:Our data propose that suppression of PIK3R3 can effectively triggers apoptosis and enhances the sensitivity of the glioblastoma cells to EGFR-TKI erlotinib. Thus, PIK3R3 can be a potential therapeutic target in glioblastoma patients.
Highlights
Glioblastoma multiform is the most aggressive form of glioma that accounts for over 50% of brain tumors (García-Claver et al, 2013; Alamdari-Palangi et al, 2020a)
The results of RT-qPCR showed that PIK3R3 Small interfering RNA (siRNA) significantly decreased the expression of the PIK3R3 mRNA in glioblastoma cells in a time-dependent way
Treatment with negative control (NC) siRNA had an insignificant effect on the expression of PIK3R3 in comparison with the blank control
Summary
Glioblastoma multiform is the most aggressive form of glioma that accounts for over 50% of brain tumors (García-Claver et al, 2013; Alamdari-Palangi et al, 2020a). Despite all medical efforts in recent years, glioma indicates a high resistance to treatment, and patients show a low rate of survival, which underlines the need for effective therapies (Mellinghoff et al, 2005; Ruano et al, 2008; García-Claver et al, 2013; Alamdari-Palangi et al, 2020b). Over-expression of EGFR gene has been extensively observed in different types of human malignant cells, including glioma. In these tumors, EGFR signaling can be restrained at the level of the receptor or through down-stream signaling mediators like PI3K/ protein kinase B (PKB)/AKT pathway (Paul et al, 2013; Oprita et al, 2021). Conclusions: Our data propose that suppression of PIK3R3 can effectively triggers apoptosis and enhances the sensitivity of the glioblastoma cells to EGFR-TKI erlotinib. PIK3R3 can be a potential therapeutic target in glioblastoma patients
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