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Benzyl isothiocyanate causes FoxO1-mediated autophagic death in human breast cancer cells

Xiao, D and Bommareddy, A and Kim, SH and Sehrawat, A and Hahm, ER and Singh, SV (2012) Benzyl isothiocyanate causes FoxO1-mediated autophagic death in human breast cancer cells. PLoS ONE, 7 (3).

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Abstract

Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, inhibits growth of breast cancer cells but the mechanisms underlying growth inhibitory effect of BITC are not fully understood. Here, we demonstrate that BITC treatment causes FoxO1-mediated autophagic death in cultured human breast cancer cells. The BITC-treated breast cancer cells (MDA-MB-231, MCF-7, MDA-MB-468, BT-474, and BRI-JM04) and MDA-MB-231 xenografts from BITC-treated mice exhibited several features characteristic of autophagy, including appearance of double-membrane vacuoles (transmission electron microscopy) and acidic vesicular organelles (acridine orange staining), cleavage of microtubule-associated protein 1 light chain 3 (LC3), and/or suppression of p62 (p62/SQSTM1 or sequestosome 1) expression. On the other hand, a normal human mammary epithelial cell line (MCF-10A) was resistant to BITC-induced autophagy. BITC-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was partially but statistically significantly attenuated in the presence of autophagy inhibitors 3-methyl adenine and bafilomycin A1. Stable overexpression of Mn-superoxide dismutase, which was fully protective against apoptosis, conferred only partial protection against BITC-induced autophagy. BITC treatment decreased phosphorylation of mTOR and its downstream targets (P70s6k and 4E-BP1) in cultured MDA-MB-231 and MCF-7 cells and MDA-MB-231 xenografts, but activation of mTOR by transient overexpression of its positive regulator Rheb failed to confer protection against BITC-induced autophagy. Autophagy induction by BITC was associated with increased expression and acetylation of FoxO1. Furthermore, autophagy induction and cell growth inhibition resulting from BITC exposure were significantly attenuated by small interfering RNA knockdown of FoxO1. In conclusion, the present study provides novel insights into the molecular circuitry of BITC-induced cell death involving FoxO1-mediated autophagy. © 2012 Xiao et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Xiao, D
Bommareddy, A
Kim, SH
Sehrawat, Aans164@pitt.eduANS164
Hahm, EReuh2@pitt.eduEUH2
Singh, SVsvs2@pitt.eduSVS2
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLisanti, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 22 March 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0032597
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
MeSH Headings: Acetylation; Animals; Autophagy--drug effects; Autophagy--physiology; Breast Neoplasms--pathology; Cell Line; Cell Line, Tumor; Female; Forkhead Transcription Factors--physiology; Humans; Isothiocyanates--pharmacology; Mice; Superoxide Dismutase--metabolism; TOR Serine-Threonine Kinases; Transplantation, Heterologous
Other ID: NLM PMC3310839
PubMed Central ID: PMC3310839
PubMed ID: 22457718
Date Deposited: 13 Sep 2012 20:15
Last Modified: 05 Feb 2019 03:55
URI: http://d-scholarship.pitt.edu/id/eprint/14159

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