Modulation of ~-catenin, Hsp27 and caveolin-1 by cadmium in HeLa cells.

ALVAREZ OLMEDO DG; CUELLO CARRIÓN FD; MARTINIS E.; WUILLOUD R; GIBERT B; ARRIGO P; CIOCCA D.R.; FANELLI M.A.

Simposio; Heat Shock Proteins in cancer and immunology; 2010

The metal cadmium (Cd) is an environmental pollutant that enters the body through dietand/or through cigarette smoke. It has been classified as a class 1 carcinogenassociated with different human cancer types. It works in all stages of the oncogenicprocess through multiple non-exclusive mechanisms that affect different intracellularpathways. Cd is the best charaderized metalloestrogen, acting via estrogen Receptor a(ERa). Also, ER-independent pathways are affeded by Cd. At the level of distal proximaltubule cells, Cd induced disruption of adherens junctions mediated by E-cadherin, ~-catenin was translocated to the cytosol and nucleus promoting cell proliferation andimpeding apoptosis. Previously, we have demonstrated that ~-catenin was associatedwith Hsp27 and caveolin-1 in human breast cancer biopsies, and that ~-catenin wasrelated with the disease prognosis. The aim of this study was to evaluate the effects ofCd on survival and apoptosis by modulating the expression and localization of ~-catenin,Hsp27 and caveolin-1 in an ERa-negative cellline. We studied HeLa cells underdifferent CdCI2 concentrations (O, 1, 5, 10, 25, 50, 100 f.lM),the cells were exposedduring three hours. Cytotoxicity was evaluated by MTT and clonogenic assay. Thelocalization and expression levels of ~-catenin, Hsp27 and caveolin-1 were evaluated byimmunocytochemistry and Western blots (in total protein extracts, cytosolic and nuclearfractions). Apoptosis was assessed by the TUNEL and BaxlBcI-2 ratio. We found that Cdtreatment reduced the cell viability to 26% and drastically reduced colony formationstarting from 5 f.lMCdCI2 and induced significant changes in the levels of the proteinsstudied. The localization of ~-catenin was modified and its expression increased in thecytoplasm. The BaxlBcI-2 ratio significantly decreased (i 1) with respect to control. HeLacells transfected with HSh27-2.2 (highly Hsp27-depleted) showed nuclear ~-cateninlocalization at low Cd levels. Cadmium would be modulating the express ion andlocalization of ~-catenin, Hsp27 and caveolin-1 in ER-negative cells affecting innateabilities such as colony formation without inhibiting completely their viability. Hsp27seems to interfere with nuclear beta 3-catenin translocation.