Hippo Pathway in Regulating Drug Resistance of Glioblastoma

Abstract

Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.

Silencing GMPPB Inhibits the Proliferation and Invasion of GBM via Hippo/MMP3 Pathways

“…Conversely, we found that overexpression of GMPPB in GBM decreases the expression of MST1/2 and inhibits the phosphorylation of MOB1, causing the unphosphorylated YAP to escape from the cytoplasm and enter the nucleus, where it binds its transcriptional coactivator (TEAD). Our results build upon and extend previous findings that the interaction of YAP-TEAD prompts cancer cells to act as cancer stem cells, initiating DNA replication procedures, and triggering tumor proliferation, progression, and metastasis [28,30,40,45]. Despite the contributions provided by our study, the direct link between GMPPB and the Hippo pathway remains elusive, although there are multiple reports providing important clues.…”

“…The Hippo pathway has been mapped out over the last several decades of study [26,27]. Two key proteins involved in transcriptional control of the Hippo pathway, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), have been implicated in the progression of multiple human cancers [28,29], including GBM tumorigenesis and multi-drug resistance [30,31]. Matrix metalloproteinases (MMPs) are a group of enzymes that are shown to mediate carcinogenesis in both a physiological and pathological manner [32].…”

Hypoxia-elicited Exosomes Promote the Chemoresistance of Pancreatic Cancer Cells by Transferring LncROR via Hippo Signaling

“…Abnormal YAP activation in the Hippo pathway significantly reduced the efficacy of targeted therapy and enhanced resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in lung cancer 33 . Furthermore, evidence showed that the Hippo pathway was involved in glioma progression and activation of chemoresistance mechanisms 34 . Dysregulation of the YAP/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling may be an important mechanism of intrinsic and acquired resistance to targeted therapies and chemotherapy 35 .…”

FOXP3 Contributes to TMZ Resistance, Prognosis, and Immune Infiltration in GBM from a Novel Pyroptosis-Associated Risk Signature

“…The transcription factor IRF3 is essential for innate antiviral immunity. IRF3 is a critical yes-associated protein (YAP) activator, probably involved in GBM chemoresistance via the Hippo pathway [46,47]. CD274, the gene encoding PD-L1, is commonly used in immunotherapy and presents effectiveness against many cancer types [48,49].…”