TY - JOUR
T1 - Penfluridol represses integrin expression in breast cancer through induction of reactive oxygen species and downregulation of Sp transcription factors
AU - Hedrick, Erik
AU - Li, Xi
AU - Safe, Stephen
N1 - Publisher Copyright:
©2016 AACR.
PY - 2017/1
Y1 - 2017/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-16-0451
DO - 10.1158/1535-7163.MCT-16-0451
M3 - Article
C2 - 27811009
AN - SCOPUS:85010075860
SN - 1535-7163
VL - 16
SP - 205
EP - 216
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 1
ER -