50 results found
Poursaitidis I, Wang X, Crighton T, et al., 2017, Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine, CELL REPORTS, Vol: 18, Pages: 2547-2556, ISSN: 2211-1247
Li H, Stokes W, Chater E, et al., 2016, Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer., Cell Discov, Vol: 2, ISSN: 2056-5968
Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
Pardo OE, Castellano L, Munro CE, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO REPORTS, Vol: 17, Pages: 570-584, ISSN: 1469-221X
Pardo OE, 2015, Meningioma dissemination and growth: a role for microRNAs, ONCOGENE, Vol: 34, Pages: 1743-1744, ISSN: 0950-9232
Schlegel CR, Georgiou ML, Misterek MB, et al., 2015, DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function, CELL DEATH & DISEASE, Vol: 6, ISSN: 2041-4889
Hoeland K, Boller D, Hagel C, et al., 2014, Targeting Class I-A PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma, PLOS ONE, Vol: 9, ISSN: 1932-6203
Roy R, Durie D, Li H, et al., 2014, hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: 12483-12497, ISSN: 0305-1048
Vincent EE, Elder DJE, O'Flaherty L, et al., 2014, Glycogen synthase kinase 3 protein kinase activity is frequently elevated in human non-small cell lung carcinoma and supports tumour cell proliferation., PLoS One, Vol: 9
BACKGROUND: Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC. METHODS: The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture. RESULTS: Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes. CONCLUSION: NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.
Kaliszczak M, Pardo OE, Seckl MJ, et al., 2013, HDAC6 inhibitor C1A abrogates the recruitment of the autophagic machinery and synergizes with proteasome, src kinase, and PI3K-mTOR inhibition., MOLECULAR CANCER THERAPEUTICS, Vol: 12, ISSN: 1535-7163
Lara R, Seckl MJ, Pardo OE, 2013, The p90 RSK Family Members: Common Functions and Isoform Specificity, CANCER RESEARCH, Vol: 73, Pages: 5301-5308, ISSN: 0008-5472
Pardo OE, Seckl MJ, 2013, S6K2: The Neglected S6 Kinase Family Member., Front Oncol, Vol: 3, ISSN: 2234-943X
S6 kinase 2 (S6K2) is a member of the AGC kinases super-family. Its closest homolog, S6K1, has been extensively studied along the years. However, due to the belief in the community that the high degree of identity between these two isoforms would translate in essentially identical biological functions, S6K2 has been largely neglected. Nevertheless, recent research has clearly highlighted that these two proteins significantly differ in their roles in vitro as well as in vivo. These findings are significant to our understanding of S6 kinase signaling and the development of therapeutic strategies for several diseases including cancer. Here, we will focus on S6K2 and review the protein-protein interactions and specific substrates that determine the selective functions of this kinase.
Seckl MJ, Roy R, Mauri F, et al., 2013, FGF-2 INDUCES CHEMORESISTANCE IN MODEL AND LUNG CANCER CELLS THROUGH S6K2/HNRNPA1-MEDIATED ENHANCED TRANSLATION OF ANTI-APOPTOTIC PROTEINS, JOURNAL OF THORACIC ONCOLOGY, Vol: 8, Pages: S1037-S1038, ISSN: 1556-0864
Liwak U, Thakor N, Jordan LE, et al., 2012, Tumor Suppressor PDCD4 Represses Internal Ribosome Entry Site-Mediated Translation of Antiapoptotic Proteins and Is Regulated by S6 Kinase 2, MOLECULAR AND CELLULAR BIOLOGY, Vol: 32, Pages: 1818-1829, ISSN: 0270-7306
De Laurentiis A, Pardo OE, Palamidessi A, et al., 2011, The catalytic class I-A PI3K isoforms play divergent roles in breast cancer cell migration, CELLULAR SIGNALLING, Vol: 23, Pages: 529-541, ISSN: 0898-6568
Lara R, Mauri F, Taylor H, et al., 2011, IDENTIFICATION OF RSK1 AS A KEY MODULATOR OF LUNG CANCER METASTASIS, JOURNAL OF THORACIC ONCOLOGY, Vol: 6, Pages: S514-S515, ISSN: 1556-0864
Lara R, Mauri FA, Taylor H, et al., 2011, An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis, ONCOGENE, Vol: 30, Pages: 3513-3521, ISSN: 0950-9232
Lara R, Mauri FA, Taylor H, et al., 2011, An siRNA screen identifies Rsk1 as a key modulator of lung cancer metastasis, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Rupniewska E, Mauri F, Watling D, et al., 2011, ROLE OF SRC FAMILY KINASES IN NSCLC: AUTOPHAGY INHIBITORS POTENTIATE KILLING EFFECTS OF DASATINIB, JOURNAL OF THORACIC ONCOLOGY, Vol: 6, Pages: S744-S745, ISSN: 1556-0864
Goh ETH, Pardo OE, Michael N, et al., 2010, Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 17065-17076, ISSN: 0021-9258
Rupniewska E, Watling D, Mauri FA, et al., 2010, Src family kinases in lung cancer, 21st Meeting of the European-Association-for-Cancer-Research, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 95-95, ISSN: 1359-6349
Lara R, Mauri F, Gray C, et al., 2009, An siRNA screen identifies RSK family members as key regulator of lung cancer metastasis, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472
Marinov M, Ziogas A, Pardo OE, et al., 2009, AKT/mTOR Pathway Activation and BCL-2 Family Proteins Modulate the Sensitivity of Human Small Cell Lung Cancer Cells to RAD001, CLINICAL CANCER RESEARCH, Vol: 15, Pages: 1277-1287, ISSN: 1078-0432
Pardo OE, Latigo J, Jeffery RE, et al., 2009, The Fibroblast Growth Factor Receptor Inhibitor PD173074 Blocks Small Cell Lung Cancer Growth In vitro and In vivo, CANCER RESEARCH, Vol: 69, Pages: 8645-8651, ISSN: 0008-5472
Seckl M, Pardo OE, Lara R, et al., 2009, RNAi library screen reveals RSK1 as a key regulator of lung cancer metastasis, JOURNAL OF THORACIC ONCOLOGY, Vol: 4, Pages: S559-S560, ISSN: 1556-0864
Seckl MJ, Pardo OE, Aboagye EO, et al., 2009, The FGF receptor (FGFR) inhibitor PD0173074 blocks SCLC growth in vitro and in vivo, JOURNAL OF THORACIC ONCOLOGY, Vol: 4, Pages: S385-S385, ISSN: 1556-0864
Pardo O, Downward J, Seckl MJ, 2008, Protein Complex involving PKCepsilon, BRaf and S6K2 and uses, WO 2008/078057 A1
Yuan M, Tomlinson V, Lara R, et al., 2008, Yes-associated protein (YAP) functions as a tumor suppressor in breast, CELL DEATH AND DIFFERENTIATION, Vol: 15, Pages: 1752-1759, ISSN: 1350-9047
Charles Swanton, Michela Marani, Olivier Pardo, et al., 2007, Regulators of Mitotic Arrest and Ceramide Metabolism Are Determinants of Sensitivity to Paclitaxel and Other Chemotherapeutic Drugs, Cancer Cell, Vol: 11, Pages: 498-512
Marinov M, Ziogas A, Pardo OE, et al., 2007, Akt/mTOR pathway activation and Bcl-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001 (Everolimus), MOLECULAR CANCER THERAPEUTICS, Vol: 6, Pages: 3409S-3409S, ISSN: 1535-7163
Katso RM, Pardo OE, Palamidessi A, et al., 2006, Phosphoinositide 3-Kinase C2beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms., Mol Biol Cell, Vol: 17, Pages: 3729-3744, ISSN: 1059-1524
Receptor-linked class I phosphoinositide 3-kinases (PI3Ks) induce assembly of signal transduction complexes through protein-protein and protein-lipid interactions that mediate cell proliferation, survival, and migration. Although class II PI3Ks have the potential to make the same phosphoinositides as class I PI3Ks, their precise cellular role is currently unclear. In this report, we demonstrate that class II phosphoinositide 3-kinase C2beta (PI3KC2beta) associates with the Eps8/Abi1/Sos1 complex and is recruited to the EGF receptor as part of a multiprotein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2beta stimulated Rac activity in A-431 epidermoid carcinoma cells, resulting in enhanced membrane ruffling and migration speed of the cells. Conversely, expression of dominant negative PI3KC2beta reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2beta-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2beta regulates the migration and survival of human tumor cells by distinct molecular mechanisms.
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