URTREGER Alejandro Jorge
congresos y reuniones científicas
Effect of the CIGB-300 synthetic peptide in the modulation of signaling pathways involved with malignant progression of human and murine lung tumors
ALEJANDRO J. URTREGER; STÉFANO M. CIRIGLIANO; MARÍA INÉS DÍAZ BESSONE; CAROLINA FLUMIAN; DAMIAN E. BERARDI; ELISA D. BAL DE KIER JOFFE; LAURA B. TODARO; HERNÁN FARINA
Congreso; 104th Annual Meeting of the American Associaton for Cancer Research; 2013
American Associaton for Cancer Research (AACR)
CK2 is a serine/threonine kinase involved in cell growth, survival and apoptosis. The CIGB-300 is a synthetic peptide capable of binding to CK2 substrates thus preventing the enzyme activity. In this work we have studied the effect of CIGB-300 on several signaling pathways involved in tumor progression, cell cycle, apoptosis and biological effects associated metastatic dissemination, using a model of human and murine lung cancer cell lines (H125 and 3LL respectively). CIGB-300 presented a lethal dose 50 (LD50) of 119±2.4 uM in H125 cells and 138.3±9.9 uM in 3LL cells. Throughout an Annexin V-FITC assay we could determine that CIGB-300 is a potent apoptosis inductor since the treatment with this drug induced apoptosis at a level comparable with that induced by 10 uM of etoposide. Besides, concomitantly with cell death induction, we could observe the activation of caspase-3 and decreased expression of c-myc and cyclin D1 and D2. The levels of nuclear and cytoplasmic components of the Wnt and NFkB pathways were analyzed by Western blot after treatment with CIGB-300. In the Wnt pathway, a significant decrease in nuclear b-catenin levels could be detected. Related to NFkB pathway, a decrease in the nuclear p65 levels was observed, without affecting cytoplasmic levels of the IkBa inhibitor. Both phenomena could be associated with a reduction in cell survival. Related to metastatic dissemination, we studied in vitro the effect of CIGB-300 on the modulation of the migratory capacity using a wound healing assay. CIGB-300 induced a significant reduction in the migratory potential in a dose dependent way in both 3LL cells (18.86±2.2% vs 32.99±2.7% 1/4 and 1/2 LD50 respectively) and H125 (31.73±20.08% vs 51.12±28.8% to 1/4 and 1/2 LD50 respectively). These results are in line with the reduction in urokinase secretion (28.64±0.2% vs 44.19±0.4% to 1/4 and 1/2 LD50 respectively) observed in the murine cell line 3LL treated with CIGB-300. Our results indicate that the treatment with CIGB-300 induces apoptosis and negatively modulates several signaling pathways involved in malignant progression besides affecting cell motility. This drug may become in the future a new strategy for the treatment of lung cancer, based on the blockade of different signaling pathways in lung cells.