Combined simultaneous transsphenoidal and transcranial regimen improves surgical outcomes in complex giant pituitary adenomas: a longitudinal retrospective cohort study.

BACKGROUND: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a non-combined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients. PATIENTS AND METHODS: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups. RESULTS: Out of 647 patients [298 (46.1%) women, mean age: 48.5 ± 14.0 years] with complex GPAs, 91 were in the combined group and 556 were in the noncombined group. Compared with the noncombined regimen, the combined regimen was associated with a higher probability of gross total resection [50.5% vs. 40.6%, odds ratio (OR): 2.18, 95% confidence interval (CI): 1.30-3.63, P = 0.003]. The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h ( P < 0.001) and higher surgical costs of 22,000 CNY (~ 3,000 USD, P = 0.022) compared with the noncombined approach. CONCLUSIONS: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients.

A novel peroxisome-related gene signature predicts clinical prognosis and is associated with immune microenvironment in low-grade glioma.

Low-grade glioma (LGG), a common primary tumor, mainly originates from astrocytes and oligodendrocytes. Increasing evidence has shown that peroxisomes function in the regulation of tumorigenesis and development of cancer. However, the prognostic value of peroxisome-related genes (PRGs) in LGG has not been reported. Therefore, it is necessary to construct a prognostic risk model for LGG patients based on the expression profiles of peroxisome-related genes. Our study mainly concentrated on developing a peroxisome-related gene signature for overall survival (OS) prediction in LGG patients. First, according to these peroxisome-related genes, all LGG patients from The Cancer Genome Atlas (TCGA) database could be divided into two subtypes. Univariate Cox regression analysis was used to find prognostic peroxisome-related genes in TCGA_LGG dataset, and least absolute shrinkage and selection operator Cox regression analysis was employed to establish a 14-gene signature. The risk score based on the signature was positively associated with unfavorable prognosis. Then, multivariate Cox regression incorporating additional clinical characteristics showed that the 14-gene signature was an independent predictor of LGG. Time-dependent ROC curves revealed good performance of this prognostic signature in LGG patients. The performance about predicting OS of LGG was validated using the GSE107850 dataset derived from the Gene Expression Omnibus (GEO) database. Furethermore, we constructed a nomogram model based on the gene signature and age, which showed a better prognostic power. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses showed that neuroactive ligand-receptor interaction and phagosome were enriched and that the immune status was decreased in the high-risk group. Finally, cell counting kit-8 (CCK8) were used to detect cell proliferation of U251 and A172 cells. Inhibition of ATAD1 (ATPase family AAA domain-containing 1) and ACBD5 (Acyl-CoA binding-domain-containing-5) expression led to significant inhibition of U251 and A172 cell proliferation. Flow cytometry detection showed that ATAD1 and ACBD5 could induce apoptosis of U251 and A172 cells. Therefore, through bioinformatics methods and cell experiments, our study developed a new peroxisome-related gene signature that migh t help improve personalized OS prediction in LGG patients.

Pituitary adenoma with cavernous sinus compartment penetration and intracranial extension: surgical anatomy, approach, and outcomes.

Objectives: To understand the different characteristics and growth corridors of knosp grade 4 pituitary adenomas (Knosp4PA) with cavernous sinus (CS) compartments penetration and intracranial extension, aiming to improve the safety, effectiveness, and total resection rate of surgery. Methods: A case series of 120 Knosp4PA patients with 187 invaded compartments were retrospectively reviewed. A novel surgery-relevant grading system was proposed according to the CS penetrating features. The details of approach drafting, risk prediction, and complication avoidance were analyzed and integrated through illustrated cases. Results: All enrolled tumor was Knosp4PA which was derived from Knosp subgrades 3A(62.5%) and 3B(37.5%). Based on the tumor growth pathway and its relevant features, five subclassifications of intracranial extension(n=98,81.7%) were classified, which derived from the superior (Dolenc's and Oculomotor subtype, 5% and 24.2%), lateral (Parkinson's subtype,18.3%), and posterior (cerebral peduncle and Dorello's subtype, 5.8% and 1.7%) CS compartment penetration. The size of intracranial extension is assessed by Lou's scale proposed here based on preoperative MRI characteristics. Under Lou's scale, the gross total rate (GTR) decreased (82%, 53%, 22%, and 19%) with grades increased (grade 0,1,2,3, respectively), and presents significant difference between the four groups (p=0.000), as well as between single and multiple compartments involved (p=0.001). Preoperative cranial nerve deficits included the optic nerve (53%), oculomotor nerve (24.2%), and abducent nerve (4.2%), with an overall rate of visual function improvement in 68.1%. Postoperative complications of transient diabetes insipidus, cerebrospinal fluid (CSF) leakage, and cranial nerve deficits were 6.7%, 0.8%, and 0%. No new cranial nerve deficits occurred. The mortality rate was 0.8%. Conclusion: The concept of "penetration" refines the extracavernous growth pattern, and the five intracranial subclassifications help to understand the potential extension corridors, enhancing adequate exposure and targeted resection of Knosp4PA. This grading system may benefit from its predictive and prognostic value, from which a higher GTR rate can be achieved.

Corrigendum: Endoscope-Assisted Retrosigmoid Approach for Vestibular Schwannomas with Intracanalicular Extensions: Facial Nerve Outcomes.

[This corrects the article DOI: 10.3389/fonc.2021.774462.].

A Micro-Environment Regulator for Filling the Clinical Treatment Gap after a Glioblastoma Operation.

The rapid postoperative recurrence and short survival time of glioblastoma (GBM) patients necessitate immediate and effective postoperative treatment. Herein, an immediate and mild postoperative local treatment strategy is developed that regulates the postoperative microenvironment and delays GBM recurrence. Briefly, an injectable hydrogel system (imGEL) loaded with Zn(II)2 -AMD3100 (AMD-Zn) and CpG oligonucleotide nanoparticles (CpG NPs) is injected into the operation cavity, with long-term function to block the recruitment of microglia/ macrophages and activate cytotoxic T cells. The finding indicated that the imGEL can regulate the immune microenvironment, inhibit GBM recurrence, and gain valuable time for subsequent adjuvant clinical chemotherapy.

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17.

Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo. Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.

Endoscope-Assisted Retrosigmoid Approach for Vestibular Schwannomas With Intracanalicular Extensions: Facial Nerve Outcomes.

OBJECTIVE: To explore the role of neuroendoscope assistance during surgical resection of the intracanalicular portion of vestibular schwannomas via the retrosigmoid approach and the subsequent early facial nerve outcomes. METHODS: Patients of vestibular schwannoma with intracanalicular extensions undergoing retrosigmoid dissection at a single institution were retrospectively analyzed in this study. Several surgical techniques were applied to ensure maximal and safe removal of tumors. Tumors extending less than 10 mm into the internal acoustic canal (IAC) were classified as Grade A, while those extending over 10 mm into IAC were taken as Grade B. Neuroendoscope was applied at the end of microscopic phase to search for potential remnants for Grade B tumors. Absolute tumor extension was defined and measured. House and Brackmann (HB) scale was used to evaluate immediate CN VII outcomes. RESULTS: Of the 61 patients, there were 38 females and 23 males. A total of 18 (29.51%) cases were Koos Grade II, 12 (19.67%) cases Koos Grade III, and 31 (50.82%) cases Koos Grade IV. There were 38 cases (62.30%) of Grade A and 23 cases (37.70%) of Grade B. Gross total resection was achieved in 60 cases (98.36%). Four cases of intracanalicular remnants were detected and completely removed under endoscopic visualizations. There was a significantly higher proportion (17%, p = 0.02) of intracanalicular remnants in Grade B than Grade A. CN VII and VIII were anatomically preserved in all cases. A total of 55 cases (90.16%) retained good (HB Grades 1 and 2) facial nerve outcomes. CONCLUSIONS: In Grade B vestibular schwannomas, after maximal microsurgical removal, endoscopic evaluation of the intracanalicular portion revealed residual tumors in 17% of the patients. Hence endoscopic evaluation of the potential intracanalicular remnants for tumor extending over 10 mm within IAC (Grade B) is recommended.

Endoscopic endonasal resection of sinonasal teratocarcinosarcoma with intracranial breakthrough: illustrative case.

BACKGROUND: Teratocarcinosarcoma traversing the anterior skull base is rarely reported in literature. The heterogenous and invasive features of the tumor pose challenges for surgical planning. With technological advancements, the endoscopic endonasal approach (EEA) has been emerging as a workhorse of anterior skull base lesions. To date, no case has been reported of EEA totally removing teratocarcinosarcomas with intracranial extensions. OBSERVATIONS: The authors provided an illustrative case of a 50-year-old otherwise healthy man who presented with left-sided epistaxis for a year. Imaging studies revealed a 31 × 60-mm communicating lesion of the anterior skull base. Gross total resection via EEA was achieved, and multilayered skull base reconstruction was performed. LESSONS: The endoscopic approach may be safe and effective for resection of extensive teratocarcinosarcoma of the anterior skull base. To minimize the risk of postoperative cerebrospinal fluid leaks, multilayered skull base reconstruction and placement of lumbar drainage are vitally important.

Initiating TrkB/Akt Signaling Cascade Preserves Blood-Brain Barrier after Subarachnoid Hemorrhage in Rats.

The integrity of the blood-brain barrier (BBB) plays a vital role in affecting the prognosis of subarachnoid hemorrhage (SAH). This study aimed to investigate activation of the Tropomyosin-related kinase receptor B (TrkB) and its downstream signaling pathway on preserving BBB breakdown after experimental SAH. An endovascular perforation SAH model was applied. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2- oxopiperidine-3-carboxamide (HIOC), the derivative of N-acetyl serotonin (NAS), was intracerebroventricularly administered 3 h after SAH induction. The neurologic scores and brain water content were evaluated in an outcome study. Western blot and immunofluorescence staining were used to investigate the mechanism. The results indicated that HIOC activated the TrkB/Akt pathway, increased the tight junction expression, improved neurologic deficits, and ameliorated brain edema after SAH. Thus, we conclude that initiating the TrkB/Akt signaling cascade preserves BBB breakdown after experimental SAH in rats.

Multimodality Imaging for Navigation in Endoscopic Transsphenoidal Surgeries.

BACKGROUND AND STUDY AIMS: Computed tomography (CT) and magnetic resonance image (MRI) data have been widely used to for navigation in various neurosurgical operations. However, delicate intracranial structures cannot be displayed using only one imaging method. Navigation with multimodality imaging was developed to better visualize these structures in glioma removal, but whether it is useful in endoscopic transsphenoidal surgery is unknown. We describe our clinical experience using multimodality imaging for navigation in endoscopic transsphenoidal surgeries. MATERIAL AND METHODS: A total of 134 patients underwent endoscopic transsphenoidal surgery with navigation using multimodality imaging. CT and MR images were fused and processed to optimally visualize anatomical structures of the sphenoidal sinus and tumor. RESULTS: Navigation with multimodality imaging offers a precise display of anatomical structures in the sphenoid sinus as compared with navigation based on either CT or MRI. CONCLUSION: Navigation with multimodality imaging is capable of providing optimized guidance during endoscopic transsphenoidal surgeries. The fused images allow precise visualization of sphenoidal sinus structures, lesions and tumors. This is valuable for increasing safety in cases of anatomical variations and potentially decreasing the rate of tumor recurrence.

Transcription factor PU.1 is involved in the progression of glioma.

Glioma is a severe disease of the central nervous system. Although previous studies have identified the important role of the immune response in association with tumor intervention, it is still unknown whether PU.1, a transcription factor known for its role in myeloid differentiation and immune responses, is involved in the progression of glioma. In the present study, we found a significant increase in SPI1, the gene that encodes PU.1, in samples from patients with glioma. Through genotype-phenotype association analysis several candidate factors that may mediate the role of PU.1 in glioma were identified. To further validate the association between PU.1 and glioma we found that the expression of BTK, a potential target of PU.1, was also upregulated in patients with glioma. We also demonstrated that various biological pathways could be involved in PU.1-associated glioma by analyzing these potential targets in the Reactome database. These results provide evidence that PU.1 could serve a role in the progress of glioma through its transcriptional targets in multiple signaling pathways. Therefore, in addition to its role in hematopoietic linage development and leukemia, PU.1 appears to be involved in the regulation of glioma and potentially in other malignant cancers.

Biomimetic Human Serum Albumin Nanoparticle for Efficiently Targeting Therapy to Metastatic Breast Cancers.

Triple-negative breast cancers (TNBCs), devoid of hormone receptors and human epidermal growth-factor receptor-2/Neu expression, bring about poor prognosis and induce a high rate of systematic metastases. The ineffectiveness of current therapies on TNBCs could be attributed to the lack of efficient targeted therapy. Paclitaxel (PTX) is considered one of first-line chemotherapeutics for TNBC treatment but, due to its low aqueous solubility and nonspecific accumulation, results in poor antitumor efficacy. The present study is aimed at enhancing the chemotherapeutic potency of PTX by improving the stability and targeting efficiency of PTX-loaded nanoparticulate drug carriers. Here, PTX was incorporated in nontoxic and endogenous material, human serum albumin (HSA), via an innovative disulfide reduction method to construct HSA-based PTX nanoparticle (HSA-PTX NP) to not only realize redox-responsive drug release but also improve in vivo stability. Besides, W peptide was selected as a target ligand to be conjugated with HSA-PTX NP for endowing active targeting ability. The resulting Wpep-HSA-PTX NP possessed a spherical structure (118 nm), 9.87% drug-loading content, and 86.3% entrapment efficiency. An in vitro drug release test showed that PTX release from Wpep-HSA-PTX NP was of a redox-responsive manner. Furthermore, cellular uptake of Wpep-HSA-PTX NP was significantly enhanced, exhibiting the improved antiproliferation and antitube formation effects of PTX in vitro. In comparison with those commercial formulations and conventional HSA NP, Wpep-HSA-PTX NP exhibited better pharmacokinetic behaviors and tumor homing characteristics. The antitumor efficacy of Wpep-HSA-PTX NP was further confirmed by the strong pro-apoptotic effect and reduced tumor burden. In a word, this evidence highlighted the proof of concept for Wpep-HSA NP as a promising conqueror to the ineffectiveness of TNBC therapy.

Long noncoding RNA FTX is upregulated in gliomas and promotes proliferation and invasion of glioma cells by negatively regulating miR-342-3p.

Gliomas remain a major public health challenge, posing a high risk for brain tumor-related morbidity and mortality. However, the mechanisms that drive the development of gliomas remain largely unknown. Emerging evidence has shown that long noncoding RNAs are key factors in glioma pathogenesis. qRT-PCR analysis was used to assess the expression of FTX and miR-342-3p in the different stages of gliomas in tissues. Bioinformatics tool DIANA and TargetSCan were used to predict the targets of FTX and miR-342-3p, respectively. Pearson's correlation analysis was performed to test the correlation between the expression levels of FTX, miR-342-3p, and astrocyte-elevated gene-1 (AEG-1). To examine the role of FTX in regulating proliferation and invasion of glioma cells, specific siRNA was used to knockdown FTX, and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and transwell assays were performed. Furthermore, rescue experiments were performed to further confirm the regulation of miR-342-3p by FTX. We then found that the expression of FTX and miR-342-3p was associated with progression of gliomas. FTX directly inhibited the expression of miR-342-3p, which subsequently regulates the expression of AEG-1. Collectively, FTX is critical for proliferation and invasion of glioma cells by regulating miR-342-3p and AEG-1. Our findings indicate that FTX and miR-342-3p may serve as a biomarker of glioma diagnosis, and offer potential novel therapeutic targets of treatment of gliomas.

Supramolecular amphiphiles based on cyclodextrin and hydrophobic drugs.

Herein we report a novel "supra-prodrug-type" superamphiphile design: via a redox-sensitive self-immolative linker, a hydrophobic drug molecule was labeled with an azobenzene moiety, which was designed to be capped by a hydrophilic cyclodextrin (CD) molecule. Four clinical hydrophobic drugs, 7-ethyl-10-hydroxycamptothecin (SN-38), doxorubicin (DOX), phenytoin and aliskiren, were investigated to directly participate in building a novel class of superamphiphile, in which the CD moiety plays as the hydrophilic head and the drug as the hydrophobic tail. This novel type of superamphiphile can further self-assemble into vesicular or tubular structures, characterized by transmission electron microscope (TEM), scanning electron microscope (SEM) and dynamic light scattering (DLS). The possible self-assembly mechanism is given based on multiple pieces of evidence, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and Ultraviolet-visible spectroscopy (UV-vis) results. The reconversion kinetics of the prodrug as a function of glutathione (GSH) in the presence or absence of UV irradiation is presented. Cell experiments indicate that the "supra-prodrug" can be facially endowed with a function by a simple substitution with another functionalized host. We hope this work can provide new reference in the field of drug screening, formulation and delivery.

T7 Peptide-Functionalized PEG-PLGA Micelles Loaded with Carmustine for Targeting Therapy of Glioma.

Glioma is regarded as the deadliest and most common brain tumor because of the extremely difficult surgical excision ascribed from its invasive nature. In addition, the natural blood-brain barrier (BBB) greatly restricts the therapeutics' penetration into the central nervous system. Carmustine (BCNU) is a widely used antiglioma drug in clinical applications. However, its serious complications prevent it from being applied in a clinical setting to some extent. Thus, it is urgent to explore novel BCNU delivery systems specially designed for glioma. Development of polymeric nanoparticles offers a favorable alternative to serve this purpose. Particularly, use of poly(lactic-co-glycolic acid) (PLGA) has been shown to be advantageous for its favorable biodegradability and biocompatibility, which ensure safe therapies. In this study, T7 peptide-conjugated, BCNU-loaded micelles were constructed successfully via the emulsion-solvent evaporation method. The micelles were characterized by transmission electron microscopy and dynamic light scattering in detail, and the capacity of BBB crossing was studied. The in vivo detecting results of the targeting effect using the BODIPY probe evidenced that T7-modified micelles showed a more pronounced accumulation and accumulated in the tumor more efficiently than in the unconjugated probe. Meanwhile, the targeting group exhibited the best curative effect accompanied with the lowest loss in body weight, the smallest tumor size, and an obviously prolonged survival time among the groups. In the near future, we believe the targeted delivery system specially designed for BCNU is expected to provide sufficient evidence to proceed to clinical trials.

Inhibition of autophagy induced by quercetin at a late stage enhances cytotoxic effects on glioma cells.

Glioma is the most common primary brain tumor in the central nervous system (CNS) with high morbidity and mortality in adults. Although standardized comprehensive therapy has been adapted, the prognosis of glioma patients is still frustrating and thus novel therapeutic strategies are urgently in need. Quercetin (Quer), an important flavonoid compound found in many herbs, is shown to be effective in some tumor models including glioma. Recently, it is reported that adequate regulation of autophagy can strengthen cytotoxic effect of anticancer drugs. However, it is not yet fully clear how we should modulate autophagy to achieve a satisfactory therapeutic effect. 3-Methyladenine (3-MA) and Beclin1 short hairpin RNA (shRNA) were used to inhibit the early stage of autophage while chloroquine (CQ) to inhibit the late stage. MTT assay was implemented to determine cell viability. Transmission electron microscopy, western blot, and immunohistochemistry were adopted to evaluate autophagy. Western blot, flow cytometry, and immunohistochemistry were used to detect apoptosis. C6 glioma xenograft models were established to assess the therapeutic effect (the body weight change, the median survival time, and tumor volume) in vivo. Quercetin can inhibit cell viability and induce autophagy of U87 and U251 glioma cells in a dose-dependent manner. Inhibition of early-stage autophagy by 3-MA or shRNA against Beclin1 attenuated the quercetin-induced cytotoxicity. In contrast, suppression of autophagy at a late stage by CQ enhanced the anti-glioma efficiency of quercetin. Therapeutic effect of quercetin for malignant glioma can be strengthened by inhibition of autophagy at a late stage, not initial stage, which may provide a novel opportunity for glioma therapy.

Downregulation of TRAP1 sensitizes glioblastoma cells to temozolomide chemotherapy through regulating metabolic reprogramming.

Cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the 'Warburg effect.' Here, we show that the tumor necrosis factor receptor-associated protein 1 (TRAP1) is crucial for the Warburg effect in human glioblastoma multiforme (GBM). In contrast to normal brain, GBMs show increased TRAP1 expression. We used both GBM cell lines and neurospheres derived from human GBM specimens to examine the effects of Knockdown of TRAP1 on GBM cell lines and glioma stem cells. We also used a neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after knockdown of TRAP1. Our results showed that knockdown of TRAP1 strongly decreased GBM cell proliferation and migration, inhibited neurosphere recovery, secondary neurosphere formation, and enhanced the therapeutic effect of temozolomide in neurosphere cultures. In GBM, knockdown of TRAP1 appeared to inhibit tumor growth and migration through its regulatory effects on metabolic reprogramming.

XBP1 silencing decreases glioma cell viability and glycolysis possibly by inhibiting HK2 expression.

Glioma cells rely on glycolysis to obtain energy and sustain their survival under microenvironmental stress in vivo. The mechanisms of regulation of glycolysis in glioma cells are unclear. Signaling pathway mediated by the transcription factor X box-binding protein 1 (XBP1) is one of the most important pathways of unfolded protein response which is comprehensively activated in cancer cells upon the microenvironmental stress. Here we showed that XBP1 was significantly activated in glioma tissues in vivo. XBP1 silencing resulted in decreasing of glioma cell viability and ATP/lactate production under hypoxia, which is possibly mediated by inhibition of Hexokinase II (HK2)'s expression. More importantly, XBP1 silenced glioma cells showed the decrease of tumor formation capacity. Our results revealed that XBP1s activation was involved in glioma glycolysis regulation and might be a potential molecular target for glioma treatment.

PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation.

Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.

Impact of autophagy inhibition at different stages on cytotoxic effect of autophagy inducer in glioblastoma cells.

BACKGROUND/AIMS: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a poor prognosis. Combination treatment of autophagy inducer and autophagy inhibitor may be a feasible solution to improve the therapeutic effects. However, the correlation between them is unclear. The purpose of this study was to investigate the effect of autophagy inhibition at different stages on cytotoxicity of autophagy inducers in glioblastoma cells. METHODS: Autophagy inhibition at early stage was achieved by 3-methyladenine (3-MA) or Beclin 1 shRNA. Autophagy inhibition at late stage was achieved by chloroquine (CQ) or Rab7 shRNA. Cell viability was assessed by MTT assay. Autophagy was measured using transmission electron microscopy and western blot. Apoptosis was measured using western blot and flow-cytometry. RESULTS: Inhibition of early steps of autophagy by 3-MA or Beclin 1 knockdown decreased the toxic effect of arsenic trioxide (ATO) in GBM cell lines. In contrast, blockade of autophagy flux at late stage by CQ or Rab7 knockdown enhanced the cytotoxicity of ATO, and caused accumulation of degradative autophagic vacuoles and robust apoptosis. Moreover, depletion of Beclin 1 abolished the synergistic effect of ATO and CQ by reducing autophagy and apoptosis. Combination of CQ with other autophagy inducers also induced synergistic apoptotic cell death. CONCLUSION: These results suggest that inhibition of late process of autophagy, not initial step, increases the cytotoxic effect of autophagy inducers via autophagy and apoptosis, which may contribute to GBM chemotherapy.