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Modulation of survival, cell cycle, resistance signaling pathways and metastatic potential by ethoxzolamide in human pancreatic ductal adenocarcinoma cell line (PANC-1)

Author(s):
Cintia Elisabeth Gomez Limia
Total Authors: 1
Document type: Master's Dissertation
Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
Defense date:
Examining board members:
Ana Carolina Santos de Souza Galvão; José Andréa Yunes
Advisor: Carmen Veríssima Ferreira Halder
Abstract

Pancreatic cancer is considerate the fourth-leading cause of disease malignancies-related death in the western world. About 80-90% of exocrine pancreatic cancer correspond to ductal adenocarcinoma and remains highly aggressive, invasive, potentially metastatic and highly resistant to conventional chemotherapy and radiotherapy. In this regard, novel compounds that diminish the aggressiveness behavior of pancreatic cancer cells are urgently called for. Currently the carbonic anhydrase inhibitors (CAI), aromatic and heterocyclic sulfonamides (e.g. ethoxzolamide – EZA), have been investigated as antitumoral, antiepileptic agents, among others. However, little is known about the molecular mechanisms of action of these compounds. Thus, for the first time, it has been evaluated the effect of EZA in pancreatic cancer and other types of solid tumors (melanoma and prostate cancer) that display highly aggressive phenotypes. The cells lines SKMel-103 (melanoma) and PANC-1 (pancreatic cancer) presented similar sensibility towards EZA after treatment for 48 and 72 h, however PC-3 displayed higher resistance. Considering these previous results and in view of the interest of our research group to better understand the biology of pancreatic cancer, we chosen PANC-1 cell line as model. The main goal of this study was to examine the molecular mechanism by which EZA diminished the proliferation rate and the tumoral aggressiveness of PANC-1 cells by checking the expression/function of some key biomarkers of those processes. EZA decreases PANC-1 cells viability (IC50 = 222 μM) and caused cell cycle arrest at phase G0/G1 confirmed by decreasing expression of key proteins of cell cycle, such as, cyclin D1 and CDK4. In addition, the expression of pro-survival kinase, Pim-1, associated with cell resistance and survival was markedly diminished, it was also observed reduction in the P-glycoprotein (Pgp) expression level, an important protein associated with multidrug resistance (MDR). In addition, it was observed an augment of AKT kinase activity. This activation of AKT might be related with endoplasmic reticulum (ER) stress. Interestingly, both expression and activity of metalloproteinases (MMPs) were diminished, as well as integrins αvβ3 expression and FAK activity, all of them are key proteins involved with aggressive and invasive phenotypes in pancreatic cancer cells. Our findings revealed, for the first time, the molecular details of EZA antitumoral action, which reinforce the potential of this class of compounds as interesting chemotherapeutic agents. (AU)

FAPESP's process: 11/03517-9 - Evaluation of the contribution of carbonic anhydrase for cancer cells resistance and aggressiveness
Grantee:Cintia Elisabeth Gomez Limia
Support type: Scholarships in Brazil - Master