Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the ...development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O
partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future.
Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient's median survival rate ranging from 15 to 17 months. The ...current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.
Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for ...the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H₂O₂), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Endothelial cells form the inner lining of vascular networks and maintain blood fluidity by inhibiting blood coagulation and promoting blood clot dissolution (fibrinolysis). Plasmin, the primary ...fibrinolytic enzyme, is generated by the cleavage of the plasma protein, plasminogen, by its activator, tissue plasminogen activator. This reaction is regulated by plasminogen receptors at the surface of the vascular endothelial cells. Previous studies have identified the plasminogen receptor protein S100A10 as a key regulator of plasmin generation by cancer cells and macrophages. Here we examine the role of S100A10 and its annexin A2 binding partner in endothelial cell function using a homozygous S100A10-null mouse. Compared with wild-type mice, S100A10-null mice displayed increased deposition of fibrin in the vasculature and reduced clearance of batroxobin-induced vascular thrombi, suggesting a role for S100A10 in fibrinolysis in vivo. Compared with wild-type cells, endothelial cells from S100A10-null mice demonstrated a 40% reduction in plasminogen binding and plasmin generation in vitro. Furthermore, S100A10-deficient endothelial cells demonstrated impaired neovascularization of Matrigel plugs in vivo, suggesting a role for S100A10 in angiogenesis. These results establish an important role for S100A10 in the regulation of fibrinolysis and angiogenesis in vivo, suggesting S100A10 plays a critical role in endothelial cell function.
The vascular endothelial cells line the inner surface of blood vessels and function to maintain blood fluidity by producing the protease plasmin that removes blood clots from the vasculature, a ...process called fibrinolysis. Plasminogen receptors play a central role in the regulation of plasmin activity. The protein complex annexin A2 heterotetramer (AIIt) is an important plasminogen receptor at the surface of the endothelial cell. AIIt is composed of 2 molecules of annexin A2 (ANXA2) bound together by a dimer of the protein S100A10. Recent work performed by our laboratory allowed us to clarify the specific roles played by ANXA2 and S100A10 subunits within the AIIt complex, which has been the subject of debate for many years. The ANXA2 subunit of AIIt functions to stabilize and anchor S100A10 to the plasma membrane, whereas the S100A10 subunit initiates the fibrinolytic cascade by colocalizing with the urokinase type plasminogen activator and receptor complex and also providing a common binding site for both tissue-type plasminogen activator and plasminogen via its C-terminal lysine residue. The AIIt mediated colocalization of the plasminogen activators with plasminogen results in the rapid and localized generation of plasmin to the endothelial cell surface, thereby regulating fibrinolysis.
Glioblastoma (GB) is the most common and deadly type of primary malignant brain tumor with an average patient survival of only 15–17 months. GBs typically have hypoxic regions associated with ...aggressiveness and chemoresistance. Using patient derived GB cells, we characterized how GB responds to hypoxia. We noted a hypoxia-dependent glycolytic switch characterized by the up-regulation of HK2, PFKFB3, PFKFB4, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CAIX, and SLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM, ANGPTL4, and SERPINE1/PAI-1 were up-regulated during hypoxia. We detected the hypoxic induction of invasion proteins, including the plasminogen receptor, S100A10, and the urokinase plasminogen activator receptor, uPAR. Furthermore, we observed a hypoxia-dependent up-regulation of the autophagy genes, BNIP-3 and DDIT4 and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of EGR1 and TFRC (Graphical abstract). Analysis of GB patient cohorts’ revealed differential expression of these genes in patient samples (except SLC16A3) compared to non-neoplastic brain tissue. High expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, TFRC, and ADM was associated with significantly lower overall survival. Together these data provide important information regarding GB response to hypoxia which could support the development of more effective treatments for GB patients.
Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or ...sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
Mechanism of plasmin generation by S100A10 Miller, Victoria A.; Madureira, Patricia A.; Kamaludin, Ain Adilliah ...
Thrombosis and haemostasis,
2017, Letnik:
56, Številka:
6
Journal Article
Recenzirano
Summary
Plasminogen (Pg) is cleaved to form plasmin by the action of specific plasminogen activators such as the tissue plasminogen activator (tPA). Although the interaction of tPA and Pg with the ...surface of the fibrin clot has been well characterised, their interaction with cell surface Pg receptors is poorly understood. S100A10 is a cell surface Pg receptor that plays a key role in cellular plasmin generation. In the present report, we have utilised domain-switched/deleted variants of tPA, truncated plasminogen variants and S100A10 site-directed mutant proteins to define the regions responsible for S100A10-dependent plasmin generation. In contrast to the established role of the finger domain of tPA in fibrin-stimulated plasmin generation, we show that the kringle-2 domain of tPA plays a key role in S100A10-dependent plasmin generation. The kringle-1 domain of plasminogen, indispensable for fibrin-binding, is also critical for S100A10-dependent plasmin generation. S100A10 retains activity after substitution or deletion of the carboxyl-terminal lysine suggesting that internal lysine residues contribute to its plasmin generating activity. These studies define a new paradigm for plasminogen activation by the plasminogen receptor, S100A10.
The microtubule-targeting compound paclitaxel is often used in the treatment of endocrine-resistant or metastatic breast cancer. We have previously shown that apoptosis of breast cancer cells in ...response to paclitaxel is mediated by induction of FOXO3a expression, a transcription factor downstream of the phosphatidylinositol-3-kinase/Akt signaling pathway. To further investigate its mechanism of action, we treated MCF-7 cells with paclitaxel and showed a dose-dependent increase in nuclear localization of FOXO3a, which coincided with decreased Akt signaling but increased c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) activity. Flow cytometry revealed that paclitaxel-induced apoptosis of MCF-7 cells and of other paclitaxel-sensitive breast cancer cell lines was maintained in the presence of inhibitors of p38 (SB203580) or mitogen-activated protein/ERK kinase 1 signaling (PD98059) but abrogated when cells were treated with the JNK1/2 inhibitor SP600125. SP600125 reversed Akt inhibition and abolished FOXO3a nuclear accumulation in response to paclitaxel. Moreover, conditional activation of JNK mimicked paclitaxel activity and led to dephosphorylation of Akt and FOXO3a. Furthermore, mouse embryonic fibroblasts (MEF) derived from JNK1/2 knockout mice displayed very high levels of active Akt, and in contrast to wild-type MEFs, paclitaxel treatment did not alter Akt activity or elicit FOXO3a nuclear translocation. Taken together, the data show that cell death of breast cancer cells in response to paclitaxel is dependent upon JNK activation, resulting in Akt inhibition and increased FOXO3a activity.
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