Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors.
It was recently demonstrated the penfluridol inhibited breast tumor growth and metastasis and this was associated with downregulation of α6- and β4-integrins. In this study, we observed the penfluridol induced reactive oxygen species (ROS) and this was the primary mechanism of action. Penfluridol-mediated growth inhibition, induction of apoptosis, and inhibition of breast cancer cell migration was attenuated after cotreatment with glutathione. Penfluridol also downregulated Sp transcription factors Sp1, Sp3, and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated miRNAs (miR27a and miR20a/miR17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4. α6- and β4-integrins as well as α5- and β1-integrins are Sp-regulated genes that are also coregulated by the orphan nuclear receptor NR4A1 and these integrins can be targeted by agents such as penfluridol that suppress Sp1, Sp3, and Sp4 and also by NR4A1 antagonists. Mol Cancer Ther; 16(1); 205-16. ©2016 AACR.
Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, Texas.
Erik
E
Hedrick
Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, Texas.
Xi
X
Li
Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, Texas ssafe@cvm.tamu.edu.
Stephen
S
Safe
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D016023:Integrins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D010395:Penfluridol / Q000494:pharmacology*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051703:Sp Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D016335:Zinc Fingers
D016023:Integrins; D035683:MicroRNAs; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017382:Reactive Oxygen Species; D051703:Sp Transcription Factors; D010395:Penfluridol