Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents

Indira Jutooru; Aaron S Guthrie; Gayathri Chadalapaka; Satya Pathi; KyoungHyun Kim; Robert Burghardt; Un-Ho Jin; Stephen Safe

doi:10.1128/MCB.01602-13

Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents

Mol Cell Biol. 2014 Jul;34(13):2382-95. doi: 10.1128/MCB.01602-13. Epub 2014 Apr 14.

Authors

Indira Jutooru¹, Aaron S Guthrie², Gayathri Chadalapaka¹, Satya Pathi¹, KyoungHyun Kim³, Robert Burghardt⁴, Un-Ho Jin⁵, Stephen Safe⁶

Affiliations

¹ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
² Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas, USA.
³ Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.
⁴ Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
⁵ Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, USA.
⁶ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, USA [email protected].

Abstract

Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticarcinogenic Agents / pharmacology*
Apoptosis / genetics
Cell Line, Tumor
Cell Proliferation
Down-Regulation / drug effects
Enzyme Inhibitors / pharmacology*
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Isothiocyanates / pharmacology*
Mice
Mice, Nude
MicroRNAs / biosynthesis
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / pathology
Proto-Oncogene Proteins c-myc / genetics
RNA Interference
RNA, Small Interfering
Reactive Oxygen Species / metabolism*
Repressor Proteins / biosynthesis
Repressor Proteins / genetics
Sp1 Transcription Factor / biosynthesis
Sp1 Transcription Factor / genetics
Sp3 Transcription Factor / biosynthesis
Sp4 Transcription Factor / biosynthesis
Xenograft Model Antitumor Assays

Substances

Anticarcinogenic Agents
Enzyme Inhibitors
Isothiocyanates
MIRN17 microRNA, human
MIRN20a microRNA, human
MIRN27 microRNA, human
MYC protein, human
MicroRNAs
Proto-Oncogene Proteins c-myc
RNA, Small Interfering
Reactive Oxygen Species
Repressor Proteins
Sp1 Transcription Factor
Sp4 Transcription Factor
ZBTB10 protein, human
ZBTB34 protein, human
ZBTB4 protein, human
Sp3 Transcription Factor
phenethyl isothiocyanate

Grants and funding

P30 ES023512/ES/NIEHS NIH HHS/United States