The Role of Micro RNAs in Regulating PI3K/AKT Signaling Pathways in Glioblastoma

Abstract

Glioblastoma is a type of brain cancer with aggressive and invasive nature. Such features result from increased proliferation and migration and also poor apoptosis of glioma cells leading to resistance to current treatments such as chemotherapy and radiotherapy. In recent studies, micro RNAs have been introduced as a novel target for treating glioblastoma via regulation of apoptotic signaling pathway, remarkably PI3K/AKT, which affect cellular functions and blockage or progression of the tumor. In this review, we focus on PI3K/AKT signaling pathway and other related apoptotic processes contributing to glioblastoma and investigate the role of micro RNAs interfering in apoptosis, invasion and proliferation of glioma through such apoptotic processes pathways. Databases NCBI, PubMed, and Web of Science were searched for published English articles using keywords such as 'miRNA OR microRNA', 'Glioblastoma', 'apoptotic pathways', 'PI3K and AKT', 'Caspase signaling Pathway' and 'Notch pathway'. Most articles were published from 7 May 2015 to 16 June 2020. This study focused on PI3K/AKT signaling pathway affecting glioma cells in separated subparts. Also, other related apoptotic pathways as the Caspase cycle and Notch have been also investigated. Nearly 40 miRNAs were found as tumor suppressors or onco-miRNA, and their targets, which regulated subcomponents participating in proliferation, invasion, and apoptosis of the tumoral cells. Our review reveals that miRNAs affect key molecules in signaling apoptotic pathways, partly PI3K/AKT, making them potential therapeutic targets to overcome the tumor. However, their utility as a novel treatment for glioblastoma requires further examination and investigation.

Keywords: Glioblastoma; Micro RNA; PI3K/AKT pathway.

Fig. 1

The flow diagram of excluding articles

Fig 2.

A schematic representation of PI3K/AKT, RAS/MAPK, and FAK/ROS signaling pathways participates in glioblastoma. They can activate by EGFR (Epidermal Growth Factor Receptor) and c-MET (Mesenchymal epithelial transition factor). The main pathway is PI3K/AKT, which activates other downstream glioma cells and affects apoptosis. The activation of PI3K results in phosphorylation of the PIP2 to generate PIP3. PIP3 activates PDK1 and, in turn, phosphorylates AKT. PTEN dephosphorylates PIP3 to PIP2 and acts as an antagonist of the PIP3 pathway. miRNAs indicating in frame affect their particular targets in these pathways, whether inhibition (showed by ┴) or inducing (showed by →).

Fig. 3

Schematic highlighting the mTOR complexes pathways and their downstream affect apoptosis in glioblastoma. TSC1 (Tuberous Sclerosis protein 1) and TSC2 can form a heterodimeric complex that inhibits the mTOR signaling pathway. RAPTOR and RICTOR are the main components of mTORC1 and mTORC2, respectively. The mTORC1 regulates protein synthesis by phosphorylating S6K1 and 4E-BP1, while mTOR2 affects gene expression, including SOX2, leading to cellular survival and tumor development

Fig. 4

Schematic representation of apoptosis inhibition by AKT signaling pathway and its downstream effectors. Akt activates MDM2, which inhibits p53 via binding to this protein. P53 is a tumor suppressor that induces apoptosis by activating some downstream as p21 and BAX. Akt activation can trigger the IKKB, which decreases IκB as an inhibitor of NF-κB. IκB reduction allows NF-κB to move to the nucleus and activate the transcription of cell survival and apoptosis inhibitors, including the surviving and Bcl2 family