Inhibition of translocator protein 18 kDa suppressed the progression of glioma via the ELAV-like RNA-binding protein 1/MAPK-activated protein kinase 3 axis

Abstract

Glioma is the most common primary malignant brain tumors in adults. Despite considerable advances in treatment, the clinical outcome remains dismal. Translocator protein 18 kDa (TSPO), an evolutionarily conserved transmembrane protein, has always been found to be elevated in glioma, which predicts a poor prognosis. However, studies on the regulatory network of TSPO in glioma are limited. The Cancer Genome Atlas (TCGA) and our research group cohorts demonstrated that TSPO expression was also highly expressed in glioma tissues and glioma cell lines. Inhibition of TSPO expression significantly reduced glioma cell proliferation and mobility in vitro . Suppression of TSPO decreased the expression of MAPK-activated protein kinase 3 (MAPKAPK3) and increased the degradation rate of its mRNA. TSPO directly interacts with ELAV1-like RNA-binding protein 1 (HUR) and promotes the nuclear–cytoplasmic shuttling of HUR. Inhibition of HUR decreased MAPKAPK3 expression and cell proliferation and mobility, whereas overexpression of MAPKAPK3 reversed the effects. Overexpression of HUR in TSPO-knockdown cells enhanced the mRNA stability of MAPKAPK3. Furthermore, rescue experiments show that the HUR/MAPKAPK3 axis accounts for the TSPO-mediated effects on glioma cell proliferation and mobility. Together, our present study indicated that TSPO may promote the nuclear–cytoplasmic shuttling of HUR, thus increasing the mRNA stability of MAPKAPK3 and promoting the proliferation and mobility of glioma cells. The HUR/MAPKAPK3 axis may be key targets for blocking the effects of TSPO and may contribute to glioma therapy.

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution

“…However, since TSPO-PET signals allow prognostication of overall survival 34 , TSPO-PET still adds valuable biomarker features to the toolbox of glioblastoma imaging assessments 35 . These quantitative TSPO-PET data even exceeded the prognostic value of gene expression levels 36 , which could be related to the direct quantification of TSPO receptor abundance instead of indirect mRNA measures. The pilot dataset of in vitro scRadiotracing in patients with glioma already showed feasibility even with small amounts of tissue obtained from biopsy.…”

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution

“…However, since TSPO-PET signals are associated with survival times in patients with primary and recurrent glioma (38,39), TSPO-PET still adds valuable biomarker features to the toolbox of glioblastoma imaging assessments (40). These quantitative TSPO-PET data even exceeded the prognostic value of gene expression levels (41), which could be related to the direct quantification of TSPO receptor abundance instead of indirect mRNA measures. In general, PET imaging is increasingly used for the assessment of patients with brain tumors, in addition to conventional MRI and provides clinically valuable information (40).…”

Characteristic Evaluation of a 11C-Labeled Leucine Analog, l-α-[5-11C]methylleucine, as a Tracer for Brain Tumor Imaging by Positron Emission Tomography

“…37 However, it is also known that the TSPO expression is high in several tumor cells, including U87MG cells. 38 (S)-11 C-KTP-Me is developed in our laboratory as a specific PET tracer for cyclooxygenase-1 (COX-1), which is a rate-limiting enzyme in the synthesis of proinflammatory prostanoids from arachidonic acid and is proven to be useful detection of neuroinflammation. 25 Since, in U87MG cells, it is reported that the expression of COX-1 is at a very low level, 39 it is highly likely that inflammation and tumors can be distinguishable when using by (S)-11 C-KTP-Me but not by TSPO ligands.…”

“…Therefore, developing a new tracer that can distinguish between tumors and inflammation is desired. ,− In neuroinflammation PET imaging, TSPO PET ligands, such as 18 F-DPA-714 and [ 11 C]­PBR28, are widely used . However, it is also known that the TSPO expression is high in several tumor cells, including U87MG cells . ( S )- 11 C-KTP-Me is developed in our laboratory as a specific PET tracer for cyclooxygenase-1 (COX-1), which is a rate-limiting enzyme in the synthesis of proinflammatory prostanoids from arachidonic acid and is proven to be useful detection of neuroinflammation .…”