TY - JOUR
T1 - Benzyl isothiocyanate (BITC) induces reactive oxygen species-dependent repression of STAT3 protein by down-regulation of specificity proteins in pancreatic cancer
AU - Kasiappan, Ravi
AU - Jutooru, Indira
AU - Karki, Keshav
AU - Hedrick, Erik
AU - Safe, Stephen
N1 - Funding Information:
This work was supported by National Institutes of Health Grant P30-ES023512 (to S. S.), a College of Veterinary Science and Biomedical Sciences postdoctoral research grant (to R. K.), and a Texas AgriLife Research and Sid Kyle endowment. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/12/30
Y1 - 2016/12/30
N2 - The antineoplastic agent benzyl isothiocyanate (BITC) acts by targeting multiple pro-oncogenic pathways/genes, including signal transducer and activator of transcription 3 (STAT3); however, the mechanism of action is not well known. As reported previously, BITC induced reactive oxygen species (ROS) in Panc1, MiaPaCa2, and L3.6pL pancreatic cancer cells. This was accompanied by induction of apoptosis and inhibition of cell growth and migration, and these responses were attenuated in cells cotreated with BITC plus glutathione (GSH). BITC also decreased expression of specificity proteins (Sp) Sp1, Sp3, and Sp4 transcription factors (TFs) and several pro-oncogenic Sp-regulated genes, including STAT3 and phospho-STAT3 (pSTAT3), and GSH attenuated these responses. Knockdown of Sp TFs by RNA interference also decreased STAT3/pSTAT3 expression. BITC-induced ROS activated a cascade of events that included down-regulation of c-Myc, and it was also demonstrated that c-Myc knockdown decreased expression of Sp TFs and STAT3. These results demonstrate that in pancreatic cancer cells, STAT3 is an Sp-regulated gene that can be targeted by BITC and other ROS inducers, thereby identifying a novel therapeutic approach for targeting STAT3.
AB - The antineoplastic agent benzyl isothiocyanate (BITC) acts by targeting multiple pro-oncogenic pathways/genes, including signal transducer and activator of transcription 3 (STAT3); however, the mechanism of action is not well known. As reported previously, BITC induced reactive oxygen species (ROS) in Panc1, MiaPaCa2, and L3.6pL pancreatic cancer cells. This was accompanied by induction of apoptosis and inhibition of cell growth and migration, and these responses were attenuated in cells cotreated with BITC plus glutathione (GSH). BITC also decreased expression of specificity proteins (Sp) Sp1, Sp3, and Sp4 transcription factors (TFs) and several pro-oncogenic Sp-regulated genes, including STAT3 and phospho-STAT3 (pSTAT3), and GSH attenuated these responses. Knockdown of Sp TFs by RNA interference also decreased STAT3/pSTAT3 expression. BITC-induced ROS activated a cascade of events that included down-regulation of c-Myc, and it was also demonstrated that c-Myc knockdown decreased expression of Sp TFs and STAT3. These results demonstrate that in pancreatic cancer cells, STAT3 is an Sp-regulated gene that can be targeted by BITC and other ROS inducers, thereby identifying a novel therapeutic approach for targeting STAT3.
UR - http://www.scopus.com/inward/record.url?scp=85007566491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007566491&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.746339
DO - 10.1074/jbc.M116.746339
M3 - Article
C2 - 27875298
AN - SCOPUS:85007566491
SN - 0021-9258
VL - 291
SP - 27122
EP - 27133
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 53
ER -