Untitled - Red TemÃ¡tica de investigaciÃ³n cooperativa en cÃ¡ncer

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O-10 INFLUENCE OF LKB1/STK11 IN GENE EXPRESSION PATTERNS INDUCED BY ENER- GY STRESS IN LUNG CANCER CELL LINES GONÇALVES RESTANI R 1 , RODRÍGUEZ NIETO S 1 , SÁNCHEZ CESPEDES M 1 1 PROGRAMA EPIGENETICA I BIOLOGIA DEL CANCER-PEBC/BELLVITGE BIOMEDICAL RESEARCH INSTI TUTE-IDIBELL BARCELONA (RD06/0020/0062) The LKB1 gene, also known as STK11 is frequently mutated or deleted in several types of cancer. Recently, it has been shown that one third of adenocarcinomas carry LKB1 somatic mutations. One of the key downstream kinases of LKB1 is the AMP-activated protein kinase (AMPK), a serine/threonine kinase that serves as a master regulator of energy metabolism. In this work, we show that upon induced energy stress either by glucose depletion or using AICAR (5-aminoimidazole-4-carboxamide-1-β-d-riboruranoside), the presence of functional LKB1 is required to regulate the expression of different genes, including the zinc finger transcriptional activator KLF15 which is involved in regulating gene expression during growth, differentiation, adipogenesis and gluconeogenesis. We observed that only those lung cancer cell lines expressing wild type LKB1 are able regulate the expression of KLF15 under energetic stress, while mutant cell lines do not have this capability. Further, we performed either down-regulation or ectopic expression of LKB1 in wild type or mutant cell lines, respectively, and confirmed these observations. In addition, upon energy stress conditions, only in LKB1 wild-type cell lines were able to restore the LKB1/AMPK pathway as evidenced by the phosphorylation of acetyl-CoA carboxylase (ACC), a target of AMPK. These observations were confirmed after ectopically restituting LKB1 in mutant cell lines. Finally, ectopic expression of a dominant negative form of AMPK’s catalytic subunit (alpha- K95R) prevented the up-regulation KLF15, demonstrating that the pathway requires a functional AMPK to control the levels of expression of KLF15. Altogether, these results show the relationship between LKB1, energy metabolism and KLF15. O-11 IDENTIFICATION OF DIFFERENTIAL GENOMIC AND PROTEOMIC PROFILES ASSO- CIATED WITH BONE METASTASES IN PROSTATE CANCER GARCÍA M 1 , RIGAU M 1 , GOMIS R 2 , MOROTE J 3 , REVENTÓS J 1 , DOLL A 1 1 RESEARCH INSTITUTE VALL HEBRON UNIVERSITY BARCELONA (RD06/0020/0058) 2 INSTITUTE FOR RESEARCH IN BIOMEDICINE, BARCELONA 3 VALL HEBRON HOSPITAL, BARCELONA (RD06/0020/0058) Bone metastases are a frequent and devastating complication in cancer patients, occurring predominantly in patients with prostate or breast cancer, but also in lung, thyroid, kidney, and stomach cancer patients. Prostate cancer (PCa) is the most common diagnosed cancer in men in western world, and skeletal metastases occur in as many as 90% of patients with advanced PCa. Bone metastatic disease, usually incurable, also has serious clinical manifestations like severe pain, pathologic fractures, hypercalcemia and spinal cord compression, making this devastating cancer complication an important and costly health issue. Objective: To identify novel molecules responsible for the bone metastatic PCa process at the miRNA, gene and protein level. Methodology: We serially performed intracardiacal injections (i.c.) of human PCa (PC-3) stably luciferase expressing cells in male nude mice in order to select a highly bone metastatic PCa cell population. Cells from bone metastasis were isolated, expanded in culture and re-injected again into another group of mice. We repeated this step three times. We used the IVIS System to monitor tumor growth and detect metastases in the living animal. Genomic and proteomic approaches were done comparing the highly bone metastatic PCa cell population to the parental one. Results: The highly bone metastatic PCa cell population obtained by in vivo selection showed an increased bone metastasis pattern when they were injected in vivo. Differential genomic profiles of specific miRNAs, genes and proteins with a FC>2 and p- value
O-12 DIOXIN RECEPTOR CONTROLS CSK-BINDING PROTEIN SIGNALING TO CAVEOLIN 1 AND Β1 INTEGRIN TO MODULATE CELL ADHESION AND MIGRATION REY-BARROSO J 1 , COLÓ GP 2 , ÁLVAREZ-BARRIENTOS A 1 , REDONDO-MUÑOZ J 2 , CARVAJAL-GONZÁ- LEZ JM 3 , MULERO-NAVARRO S 3 , GARCÍA-PARDO A 2 , TEIXIDÓ J 2 ,FERNÁNDEZ-SALGUERO PM 1 1 UNIVERSIDAD DE EXTREMADURA, BADAJOZ (RD06/0020/1016) 2 CENTRO DE INVESTIGACIONES BIOLÓGICAS (CIB), MADRID (RD06/0020/0011) 3 MOUNT SINAI SCHOOL OF MEDICINE O-13 CD44 POSITIVITY CONFERS RESISTANCE TO SORAFENIB-INDUCED CELL DEATH IN HEPATOCELLULAR CARCINOMA (HCC) CELLS FERNANDO J 1 , ÁLVAREZ-BARRIENTOS A 2 , FERNÁNDEZ-SALGUERO PM 2 , CEPEDA EB 1 , FERNÁNDEZ- RODRIGUEZ CM 3 , SANCHO P 1 , FABREGAT I 1 1 IDIBELL, BARCELONA (RD06/0020/0097) 2 UNIVERSIDAD DE EXTREMADURA BADAJOZ (RD06/0020/1016) 3 HOSPITAL UNIVERSITARIO FUNDACIÓN ALCORCÓN, MADRID Recent studies strongly support a regulatory role for the dioxin receptor (AhR) in cell adhesion and migration. Following our previous work, we report here that the C-terminal Src kinase-binding protein (Cbp)-Csk-Src pathway sustains migration of transformed fibroblasts (T-FGM) and regulates β1 integrin activation andcaveolin-1 (Cav1) tyrosine phosphorylation, and that such mechanism is AhR dependent. T-FGM AhR-/-fibroblasts had higher integrin β1 activation that coincided with higher Cbp expression, increased fibronectin secretion and impaired directional migration. Notably, interfering Cbp/Pag1 expression in AhR-/- fibroblasts rescued β1 integrin activation, migration and cell morphology. c-Src activation (Tyr 416) was inhibited, probably because the increase in Cbp/Pag1 levels produced an accumulation of inhibitory Csk- Cbp/ Pag1 complexes. Consistently, focal adhesion kinase (FAK) phosphorylation was reduced at Tyr 576 –Tyr 577. The c-Src target Cav1was hypophosphorylated at Tyr 14, and its association to c-Src diminished in AhR-/- cells. Interestingly, AhR was present at the plasma membrane in detergent resistant microdomains (DRM; rafts) and co-immunoprecipitated with Cav1 under basal cell conditions, revealing a functional link by which AhR could alter Cav1 distribution between DRM and non-DRM domains. Furthermore, AhR interference impaired directional migration and Cav1distribution. Thus, fibroblasts migration requires AhR for proper regulation of the Cbp/Pag1-dependent signaling to β1 integrin and Cav1. As Hepatocellular carcinoma (HCC) is the fifth cause of cancer-associated mortality in the West and one of the leading worldwide causes of death, exists an urge to develop efficacious tumor-targeted agents [1-4]. Existence of Cancer Stem Cells (CSCs) or Tumor Initiating Cells (TICs) was proposed forty years ago, but they have only been identified recently in liver cancers. These cells show a highly-efficient self renewal, ability to differentiate into different lineages, drug-resistance and tumor regenerating capacity [5]. Their presence might change therapeutic targeting, since effective approaches could overlook TICs elimination. In this work we have examined the expression of TIC markers, such as EpCAM, CD44 or CD90, in different HCC cell lines to establish correlations, if they exist, with the responsiveness to the first line targeted therapeutic actual option for HCC, i.e., the multikinase inhibitor sorafenib [6]. Analysis of TICs-related markers allowed us to identify a group of different HCC cell lines that were EpCAM+/CD44- and another one that were EpCAM-/CD44+. Expression of CD44 correlated with a more de-differentiated and invasive phenotype . Interestingly, CD44+ cells were much less responsive to sorafenib in terms of cell death. Targeting knock-down of CD44 with specific siRNA sensitized cells to this drug, indicating the direct role played by CD44 in conferring sorafenib resistance. These results open the possibility for a better fitness prediction to sorafenib treatment and suggest a potential targeting of CD44 combined with the use of sorafenib as a strategy on CD44-positive patients. Furthermore, we found that sorafenib could be interfering in TIC markers presentation, as the inhibitor decreased the percentage of CD90+ cells, but simultaneously increased EpCAM expression in those cells that previously expressed it. Future experiments will reveal the relevance of these effects. References: 1. Andrisani, O.M., L. Studach, and P. Merle. Semin Cancer Biol. 21(1): p. 4-9. 2. Worns, M.A. and P.R. Galle. Expert Opin Investig Drugs. 19(5): p. 615-29. 3. Luo, J.H., et al. Hepatology. 44(4): p. 1012-24. 4. Villanueva, A., et al. Annu Rev Med. 61: p. 317-28. 5. Rountree, C.B., L. Mishra, and H. Willenbring. Hepatology. 55(1): p. 298-306. 6. Llovet, J.M., et al. N Engl J Med. 359(4): p. 378-90. We acknowledge Ministerio de Economía y Competitividad, Spain, AGAUR-Generalitat de Catalunya and IDIBELL for providing research funds and also the Red Temática de Investigación Cooperativa en Cáncer, RTICC-ISCIII, for funding a mobility program that made this work possible. We are also deeply grateful to Bayer Schering Pharma AG (Berlin,Germany) for providing sorafenib. 28 29
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