Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
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Silvina Odete Bustos1, Gustavo José da Silva Pereira2, Renata de Freitas Saito1, Cristiane Damas Gil3, Daniela Bertolli Zanatta1, Soraya Soubhi Smaili2 and Roger Chammas1
1Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina de São Paulo, São Paulo, Brazil
2Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil
3Laboratory of Histology, Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
Roger Chammas, email: [email protected]
Keywords: autophagy; galectin-3; melanoma; vemurafenib; starvation
Received: October 20, 2017 Accepted: February 10, 2018 Epub: February 16, 2018 Published: March 06, 2018
Melanoma is a current worldwide problem, as its incidence is increasing. In the last years, several studies have shown that melanoma cells display high levels of autophagy, a self-degradative process that can promote survival leading to drug resistance. Consequently, autophagy regulation represents a challenge for cancer therapy. Herein, we showed that galectin-3 (Gal-3), a β-galactoside binding lectin which is often lost along melanoma progression, is a negative regulator of autophagy in melanoma cells. Our data demonstrated that Gal-3low/negative cells were more resistant to the inhibition of the activity of the cancer driver gene BRAFV600E by vemurafenib (PLX4032). Interestingly, in these cells, starvation caused further LC3-II accumulation in cells exposed to chloroquine, which inhibits the degradative step in autophagy. In addition, Gal-3 low/negative tumor cells accumulated more LC3-II than Gal-3 high tumor cells in vivo. Resistance of Gal-3low/negative cells was associated with increased production of superoxide and activation of the Endoplasmic Reticulum (ER) stress response, as evaluated by accumulation of GRP78. Pharmacological inhibition of autophagy with bafilomycin A reversed the relative resistance of Gal-3low/negative cells to vemurafenib treatment. Taken together, these results show that the autophagic flux is dependent on Gal-3 levels, which attenuate the prosurvival role of autophagy.
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