title: Targeting heat shock proteins by phenethyl isothiocyanate results in cell-cycle arrest and apoptosis of human breast cancer cells.
abstract: Heat shock proteins (HSPs) are chaperones for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSPs (27, 70, and 90) are abundantly expressed in a wide range of cancers and are transcriptionally regulated by heat shock factor (HSF1). Most of the synthetic HSP inhibitors exhibit toxicity, therefore, searching for inhibitors with limited or no toxicity will be of help. The objective of the present study was to determine the effect of natural isothiocyanate (phenethyl isothiocyanate; PEITC) on different HSPs (27, 70, and 90) and HSF1 in 2 breast cancer cell lines, namely breast adenocarcinoma MCF-7 (with wild type p53) and highly metastatic breast cancer cell MDA-MB-231 (with mutated p53). PEITC significantly inhibited the expression of HSPs (particularly HSP 90) and HSF1. Molecular consequences due to HSP inhibition were downregulation of cell-cycle regulatory proteins like Cyclin B1, CDK1, Cdc25C, PLK-1, and upregulation of p21 irrespective of p53 status. These modulations were accompanied by cell-cycle arrest at G2/M phase and apoptosis by activation of caspases 3 and 9. PEITC therefore may be regarded as a potent HSP inhibitor and an antitumor agent in the treatment of breast cancer.
authors.affiliation: Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Ruma
authors.initials: R
authors.lastname: Sarkars
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Madhumita
authors.initials: M
authors.lastname: Roy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D006360:Heat-Shock Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006360:Heat-Shock Proteins; D017879:Isothiocyanates; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C058305:phenethyl isothiocyanate; D045304:Cytochromes c