TY - JOUR
T1 - Reactive oxygen species (ROS)-inducing triterpenoid inhibits rhabdomyosarcoma cell and tumor growth through targeting SP transcription factors
AU - Kasiappan, Ravi
AU - Jutooru, Indira
AU - Mohankumar, Kumaravel
AU - Karki, Keshav
AU - Lacey, Alexandra
AU - Safe, Stephen
N1 - Funding Information:
This work was supported by grants from the NIH (grant nos. P30-ES023512, to S. Safe and T32-ES026568 to, K. Karki), the Kleberg Foundation (to S. Safe), the College of Veterinary Science and Biomedical Sciences postdoctoral research grant and the DBT-Ramalingaswami Fellowship (to R. Kasiappan), Texas AgriLife Research (to S. Safe), and the Sid Kyle endowment (to S. Safe).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Methyl 2-trifluoromethyl-3,11-dioxo-18b-olean-1,12-dien-3-oate (CF 3 DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF 3 DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF 3 DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF 3 DODA-Me–induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF 3 DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease. Implications: CF 3 DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.
AB - Methyl 2-trifluoromethyl-3,11-dioxo-18b-olean-1,12-dien-3-oate (CF 3 DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF 3 DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF 3 DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF 3 DODA-Me–induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF 3 DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease. Implications: CF 3 DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.
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U2 - 10.1158/1541-7786.MCR-18-1071
DO - 10.1158/1541-7786.MCR-18-1071
M3 - Article
C2 - 30610105
AN - SCOPUS:85063077995
SN - 1541-7786
VL - 17
SP - 794
EP - 805
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 3
ER -