Reduced expression of proteolipid protein 2 increases ER stress‐induced apoptosis and autophagy in glioblastoma

Abstract

Proteolipid protein 2 (PLP2) is an integral ion channel membrane protein of the endoplasmic reticulum. The protein has been shown to be highly expressed in many cancer types, but its importance in glioma progression is poorly understood. Using publicly available datasets (Rembrandt, TCGA and CGGA), we found that the expression of PLP2 was significantly higher in high‐grade gliomas than in low‐grade gliomas. We confirmed these results at the protein level through IHC staining of high‐grade (n = 56) and low‐grade glioma biopsies (n = 16). Kaplan‐Meier analysis demonstrated that increased PLP2 expression was associated with poorer patient survival. In functional experiments, siRNA and shRNA PLP2 knockdown induced ER stress and increased apoptosis and autophagy in U87 and U251 glioma cell lines. Inhibition of autophagy with chloroquine augmented apoptotic cell death in U87‐ and U251‐siPLP2 cells. Finally, intracranial xenografts derived from U87‐ and U251‐shPLP2 cells revealed that loss of PLP2 reduced glioma growth in vivo. Our results therefore indicate that increased PLP2 expression promotes GBM growth and that PLP2 represents a potential future therapeutic target.

Modeling of Aryl Hydrocarbon Receptor Pathway Intrinsic Immunometabolic Role using Glioblastoma Stem Cells and Patient-Derived Organoids

“…5a, b and Supplementary Table 1 ). In contrast, treatment with CH223191 robustly altered the GBMO-30 transcriptome, resulting in 771 DEGs, including several prognostically important chemokines and interleukins in GBM, such as CCL20 32 and IL1B. Network analysis demonstrated the central role of AHR in DEGs ( Fig.…”

“…Importantly, we determined that ten of the 41 genes were downregulated following AHR inhibition in GBMO-30 and significantly associated with survival supporting a role of inactivation of AHR on potential genes that drive mortality in GBM. These include PLP2 , a gene involved in autophagy and ER stress in GBM 32 ; SGMS2, which is associated with aggressive breast cancer 33 ; MT1H, which is a tumor suppressor in liver cancer 34 ; and SERPINE1 , which is associated with several cancers 35 ( Fig. 7b- e ).…”

PLP2 Expression as a Prognostic and Therapeutic Indicator in High-Risk Multiple Myeloma

“…Proteolipid protein 2 (PLP2) is an integral ion channel membrane protein of the endoplasmic reticulum (ER) [10]. While the exact function of PLP2 under normal conditions is not known, the study of the protein has revealed several features in ER.…”

“…Firstly, it is an integral membrane protein that localizes to the ER. Secondly, PLP2-knockout mice display increased ER stress in neurons under hypoxia, which leads to apoptotic cell death [11]; downregulation of PLP2 increased ER stress-induced apoptosis and reduced tumor cell survival in vitro [10]. In contrast, proteasome inhibition (bortezomib) induces ER stress due to accumulation of misfolded and unfolded proteins in the ER, which leads to myeloma cell death [12].…”

“…Recently, this protein was reported to be involved in several human cancers [13][14][15][16]. Sonoda et al demonstrated that PLP2 enhances cell proliferation, adhesion, and invasion in melanoma [15]; Xiao et al showed that PLP2 is significantly upregulated and predicts poor prognosis in renal cell carcinoma patients [17]; and Feng et al found that high PLP2 expression predicts an aggressive disease grade and a shorter survival in glioma patients [10]. However, the potential roles of PLP2 in MM remain elusive.…”