Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still ...die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
Glioblastoma (GBM) is considered one of the most aggressive human cancers. Earlier, our group have demonstrated that alternative RNA splicing plays an important role in the regulation of the GBM ...phenotype. To continue this study, we analyzed the type of RNA splicing and the expression levels of the spliceosomal genes in a large number of tumor tissue samples and patient-derived GBM sphere lines. We demonstrated that the expression level of splicing factors allows dividing GBM patients into groups with different survival prognosis and also reflects the phenotype of the tumor. In addition, we identified the alternative splicing events that may regulate the GBM phenotype. Finally, we for the first time compared the expression profiles of the spliceosomal genes in different regions of the same tumor and identified splicing factors whose expression most significantly correlates with GBM patients’ survival. Aforementioned data emphasize the important role of pre-mRNA splicing in GBM progression.
Among the many malignant neoplasms, glioblastoma (GBM) leads to one of the worst prognosis for patients and has an almost 100% recurrence rate. The only chemotherapeutic drug that is widely used for ...treating glioblastoma is temozolomide, a DNA alkylating agent. Its impact, however, is only minor; it increases patients survival just by 12 to 14 months. Multiple highly selective compounds that affect specific proteins and have performed well in other types of cancer have proved ineffective against glioblastoma. Hence, there is an urgent need for novel methods that could help achieve the long-awaited progress in glioblastoma treatment. One of the potentially promising approaches is the targeting of non-coding RNAs (ncRNAs). These molecules are characterized by extremely high multifunctionality and often act as integrators by coordinating multiple key signaling pathways within the cell. Thus, the impact on ncRNAs has the potential to lead to a broader and stronger impact on cells, as opposed to the more focused action of inhibitors targeting specific proteins. In this review, we summarize the functions of long noncoding RNAs, circular RNAs, as well as microRNAs, PIWI-interacting RNAs, small nuclear and small nucleolar RNAs. We provide a classification of these transcripts and describe their role in various signaling pathways and physiological processes. We also provide examples of oncogenic and tumor suppressor ncRNAs belonging to each of these classes in the context of their involvement in the pathogenesis of gliomas and glioblastomas. In conclusion, we considered the potential use of ncRNAs as diagnostic markers and therapeutic targets for the treatment of glioblastoma.
•Two ligands with antioxidant moieties and six complexes on their base were synthesized.•The antioxidant properties of compounds were studied.•Cytotoxity on cancer cell lines and tumor samples from ...patients was estimated.•Lead compound demonstrated IC50 = 6 nM on MCF-7 cell line.•Plausible cytotoxicity mechanism is related to promotion of tubulin polymerization.
A series of novel imidazole-containing ligands and their organotin complexes were synthesized and characterized by NMR, IR, MALDI and elemental analysis. Redox behavior was studied by cyclic voltammetry (CV). Antioxidant properties were estimated in model reactions of single-electron reduction (CUPRAC-test), scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and O2−. radical anion, enzymatic oxidation of linoleic acid by lipoxygenase and Fe3+-induced lipid peroxidation of rat liver homogenates. It was found that ligands and complexes both possess radical scavenging activity of prolonged action type. Compounds exhibited notable antioxidant activity in lipid peroxidation. Cytotoxicity was estimated in standard MTT-test on multiple cell lines. Compounds demonstrated high toxicity on colon carcinoma and breast cancer cells and based on obtained data, lead compound was proposed. Additional assays were carried out for the lead compound, including regular MTT-test on cancer cells possessing various resistant mechanisms and modified MTT-test on tumor tissue samples, obtained from patients as well as apoptosis and cell cycle studies. All organotin complexes were also studied for their influence on tubulin polymerization. It was demonstrated that obtained compounds demonstrate unorthodox activity, promoting microtubules assembly rate instead of inhibiting it. Significant influence of compound 5 on G2/M phase of cell cycle is in accordance with influence on tubulin polymerization and lets us to mark synthesized compounds as mitotic poisons. The results open up the scopes for the search of novel antitumor agents for treatment of advanced forms of cancer.
Novel organotin complexes with 2,6-di‑tert-butylphenol moieties were synthesized. Antioxidant activity of prolonged action type was demonstrated. Introduction of cytoprotective group into organotins leads to attenuation of cytotoxicity of resulting pharmacologically active agents. Display omitted
PON2 belongs to the paraoxonase protein family that consists of lactone hydrolyzing enzymes with different substrate specificities. Unlike other members of the family, PON2 exhibits substantial ...antioxidant activity, is localized predominantly inside the cell, and is ubiquitously expressed in all human tissues. Previously, it was proffered that defense against pathogens, such as
, is the main function of paraoxonases. However, recent findings have highlighted the important role played by PON2 in protection against oxidative stress, inhibition of apoptosis, and progression of various types of malignancies. In the current study, we performed a bioinformatic analysis of RNA and DNA sequencing data extracted from tumor samples taken from more than 10,000 patients with 31 different types of cancer and determined expression levels and mutations in the
gene. Next, we investigated the intracellular localization of PON2 in multiple cancer cell lines and identified the proteins interacting with PON2 using the LC-MS/MS technique. Our data indicate that a high PON2 expression level correlates with a worse prognosis for patients with multiple types of solid tumors and suggest that PON2, when localized on the nuclear envelope and endoplasmic reticulum, may protect cancer cells against unfavorable environmental conditions and chemotherapy.
Although understanding of the molecular biology of cancer has advanced and medicine has an impressive arsenal of chemotherapeutic drugs, the problem of tumor resistance to individual drugs and drug ...combinations has not yet been resolved. Known mechanisms of cancer chemoresistance do not explain the reason for such a phenomenon as “apoptosis-induced proliferation,” where cells dying under the effect of the therapy secrete some signaling molecules into the extracellular medium to promote proliferation, survival, and acquisition of a more aggressive phenotype of neighboring cancer cells. The nature of this unexpected phenomenon is only now beginning to be partially clarified, but the nature of such signaling between apoptotic cancer cells and their neighboring cells remains largely unknown. For this reason, in this review we discuss currently known types of intercellular communication of tumor cells, give specific examples of important secreted molecules involved in signaling between cancer cells, and describe possible cell interactions contributing to the progress of cancer outgrowth.
In response to the wide variety of external and internal signals, mammalian cells undergo apoptosis, programmed cell death. Dysregulation of apoptosis is involved in multiple human diseases, ...including cancer, autoimmunity, and ischemic injuries. Two types of apoptosis have been described: the caspase-dependent one, leading to digestion of cellular proteins, and caspase-independent apoptosis, resulting in DNA fragmentation. The latter type of apoptosis is executed by AIF protein and is believed to have appeared first during evolution. The key step in the caspase-independent apoptosis program is the dissociation of AIF from the outer mitochondrial membrane (OMM). However, the molecular mechanism of interaction between AIF and OMM remains poorly understood. In this study, we demonstrated that AIF can bind to OMM via mortalin protein. We confirmed interaction between AIF and mortalin both
and
and mapped the amino acid sequences that are important for the binding of these proteins. Next, we showed that apoptosis induction by chemotherapy leads to downregulation of AIF-mortalin interaction and dissociation of AIF from the OMM. Finally, a bioinformatic analysis demonstrated that a high level of mortalin expression correlates with a worse survival prognosis for glioma patients. Altogether, our data revealed that mortalin plays an important role in the regulation of the caspase-independent apoptotic pathway and allowed us to speculate that inhibition of AIF-mortalin interaction may induce a dissociation of AIF from the OMM and subsequent apoptosis of cancer cells.
Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the ...invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133+ PN signature, transition to a CD109+ MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133−/CD109+ cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.
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•Distinct types of GSCs exist in the GBM core versus the invasive edge•Gain of CD109 in tumor cells occurs at the invasive edge in response to IR•IR induced pro-inflammatory response transcriptionally regulates CD109 via C/EBP-β•CD109 drives oncogenic signaling through the YAP/TAZ pathway
Minata et al., in response to the proinflammatory environment induced by radiation, find that the tumor cells at the invasive edge acquire the expression of the CD109 protein concomitantly losing CD133. CD109 drives oncogenic signaling through the YAP/TAZ pathway, confers radioresistance to the cells, and represents a new potential therapeutic target for glioblastoma.
Glioblastoma (GBM) is characterized by exceptionally high intratumoral heterogeneity. However, the molecular mechanisms underlying the origin of different GBM cell populations remain unclear. Here, ...we found that the compositions of ribosomes of GBM cells in the tumour core and edge differ due to alternative RNA splicing. The acidic pH in the core switches before messenger RNA splicing of the ribosomal gene RPL22L1 towards the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by interacting with lncMALAT1 in the nucleus and inducing its degradation. Contrarily, in the tumour edge region, RPL22L1a interacts with ribosomes in the cytoplasm and upregulates the translation of multiple messenger RNAs including TP53. We found that the RPL22L1 isoform switch is regulated by SRSF4 and identified a compound that inhibits this process and decreases tumour growth. These findings demonstrate how distinct GBM cell populations arise during tumour growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy.
Langmuir–Blodgett lipid films and plasma membranes of glioma cells were analyzed using timeof-flight secondary ion mass spectrometry (TOF-SIMS). Bi
3
+
primary ion beam was determined to be most ...efficient in various experimental setups. TOF-SIMS was shown to be applicable for a quantitative analysis of model lipid structures, as well as plasma membranes of glioma cells U87MG in vitro. A combination of atomic-force microscopy and scanning electron microscopy yielded the depth resolution of ~10–20 nm for cell surface scanning by primary ion beam.
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