Role of apoptosis, autophagy, and the unfolded protein response in glioblastoma chemoresistance

Abstract Glioblastoma (GBM) is a rapidly progressive form of brain tumor with high mortality rates. Current treatment modalities are moderately effective and chemoresistance has become a major concern in GBM treatment. Evidence suggests that cross talks between several pathways, including apoptosis, autophagy, and unfolded protein response (UPR), are involved in the induction of resistance to chemotherapeutic agents such as temozolomide (TMZ). Apoptosis is crucial for organism survival through the elimination of unwanted cells. Various conditions such as hypoxia, defective DNA mismatch repair (MMR) system, p53 loss of function, insufficient O6-methylguanine-DNA-methyltransferase (MGMT) enzyme, and dysregulation of miRNAs expression negatively influence apoptosis and lead to chemoresistance. A dual role has been reported for autophagy in GBM chemoresistance and chemosensitivity. Similarly, the UPR adaptive pathway has both cytotoxic and cytoprotective effects on GBM cells in response to chemotherapeutic agents. Considering the complexity of this malignancy, the development of comprehensive in vitro models is required to predict the effects of different therapeutic strategies by recapitulating the intricate in vivo GBM microenvironment. Three-dimensional (3D) tissue engineering using different biomaterials is a promising approach to evaluate the effectiveness of chemotherapeutics by developing bioengineered GBM models. The functional contribution of signaling pathways such as autophagy, apoptosis, and UPR can be investigated in detail through 3D tissue engineering. In this chapter, we briefly review the role of autophagy, apoptosis, and unfolded protein response in chemoresistance in GBM and later discuss the application of a 3D bioengineer model of GBM and its application in the evaluation of chemotherapy response and chemoresistance in GBM.