title: Phenethyl isothiocyanate, by virtue of its antioxidant activity, inhibits invasiveness and metastatic potential of breast cancer cells: HIF-1α as a putative target.
abstract: Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in facilitating tumor progression and metastasis. Reducing the levels of HIF-1α might therefore be an important anticancer strategy. This could be achieved by understanding the key cellular events involved in HIF-1α activation. Present study explored the effect of phenethyl isothiocyanate (PEITC), a natural isothiocyanate, found in cruciferous vegetables on the expression of HIF-1α and HSP90 in breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) under both normoxia and hypoxia. This study established the possible role of ROS in the up-regulation of these markers in breast cancer cells. PEITC-induced nuclear accumulation of Nrf2, increased the activities of several antioxidant enzymes, and thus reduced the ROS burden of the tumor cells by acting as an indirect antioxidant. This resulted in the down-regulation of HSP90 and thereby HIF-1α expression. HSP90 was also found to be involved in the regulation of HIF-1α. A probable link between down-regulation of HIF-1α with reduction of ROS by PEITC through induction of Nrf2 was determined. Finally, our study demonstrated that modulation of HIF-1α by PEITC retarded adhesion, aggregation, migration and invasion of the breast cancer cells, thereby showing anti-metastatic effect. Activities of MMPs (2 & 9) and expression of VEGF were also altered by PEITC.
authors.affiliation: a Department of Environmental Carcinogenesis & Toxicology , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Ruma
authors.initials: R
authors.lastname: Sarkar
authors.affiliation: a Department of Environmental Carcinogenesis & Toxicology , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: b Department of Surgical Oncology , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India.
authors.forename: Jaydip
authors.initials: J
authors.lastname: Biswas
authors.affiliation: a Department of Environmental Carcinogenesis & Toxicology , Chittaranjan National Cancer Institute , Kolkata , West Bengal , India ;
authors.forename: Madhumita
authors.initials: M
authors.lastname: Roy
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000235:genetics; D017879:Isothiocyanates / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis
chemical_list: D000975:Antioxidants; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017879:Isothiocyanates; C058305:phenethyl isothiocyanate
keywords: HIF-1α; HSP90; Nrf2; PEITC; ROS