title: Proteomic profiling reveals that resveratrol inhibits HSP27 expression and sensitizes breast cancer cells to doxorubicin therapy.
abstract: The use of chemopreventive natural compounds represents a promising strategy in the search for novel therapeutic agents in cancer. Resveratrol (3,4',5-trans-trihydroxystilbilene) is a dietary polyphenol found in fruits, vegetables and medicinal plants that exhibits chemopreventive and antitumor effects. In this study, we searched for modulated proteins with preventive or therapeutic potential in MCF-7 breast cancer cells exposed to resveratrol. Using two-dimensional electrophoresis we found significant changes (FC >2.0; p≤0.05) in the expression of 16 proteins in resveratrol-treated MCF-7 cells. Six down-regulated proteins were identified by tandem mass spectrometry (ESI-MS/MS) as heat shock protein 27 (HSP27), translationally-controlled tumor protein, peroxiredoxin-6, stress-induced-phosphoprotein-1, pyridoxine-5'-phosphate oxidase-1 and hypoxanthine-guanine phosphoribosyl transferase; whereas one up-regulated protein was identified as triosephosphate isomerase. Particularly, HSP27 overexpression has been associated to apoptosis inhibition and resistance of human cancer cells to therapy. Consistently, we demonstrated that resveratrol induces apoptosis in MCF-7 cells. Apoptosis was associated with a significant increase in mitochondrial permeability transition, cytochrome c release in cytoplasm, and caspases -3 and -9 independent cell death. Then, we evaluated the chemosensitization effect of increasing concentrations of resveratrol in combination with doxorubicin anti-neoplastic agent in vitro. We found that resveratrol effectively sensitize MCF-7 cells to cytotoxic therapy. Next, we evaluated the relevance of HSP27 targeted inhibition in therapy effectiveness. Results evidenced that HSP27 inhibition using RNA interference enhances the cytotoxicity of doxorubicin. In conclusion, our data indicate that resveratrol may improve the therapeutic effects of doxorubicin in part by cell death induction. We propose that potential modulation of HSP27 levels using natural alternative agents, as resveratrol, may be an effective adjuvant in breast cancer therapy.
authors.affiliation: Carcinogenesis Laboratory, National Institute of Cancerology, Mexico City, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Díaz-Chávez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Fonseca-Sánchez
authors.forename: Elena
authors.initials: E
authors.lastname: Arechaga-Ocampo
authors.forename: Ali
authors.initials: A
authors.lastname: Flores-Pérez
authors.forename: Yadira
authors.initials: Y
authors.lastname: Palacios-Rodríguez
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Domínguez-Gómez
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Marchat
authors.forename: Lizeth
authors.initials: L
authors.lastname: Fuentes-Mera
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mendoza-Hernández
authors.forename: Patricio
authors.initials: P
authors.lastname: Gariglio
authors.forename: César
authors.initials: C
authors.lastname: López-Camarillo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D020543:Proteome; D040901:Proteomics; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D020543:Proteome; D034741:RNA, Small Interfering; D013267:Stilbenes; D004317:Doxorubicin; D000077185:Resveratrol