TY - JOUR
T1 - Quercetin enhances the anti-tumor effects of BET inhibitors by suppressing hnRNPA1
AU - Pham, Thao N.D.
AU - Stempel, Sophie
AU - Shields, Mario A.
AU - Spaulding, Christina
AU - Kumar, Krishan
AU - Bentrem, David J.
AU - Matsangou, Maria
AU - Munshi, Hidayatullah G.
N1 - Funding Information:
Funding: This work was supported by grants R01CA186885 (to H.G.M.) and R21CA220625 (to K.K.), a Merit award I01BX002922 (to H.G.M.) from the Department of Veterans Affairs, and a Translational Bridge Fellowship Award from the Robert H. Lurie Cancer Center (to T.N.D.P.).
Funding Information:
This work was supported by grants R01CA186885 (to H.G.M.) and R21CA220625 (to K.K.), a Merit award I01BX002922 (to H.G.M.) from the Department of Veterans Affairs, and a Translational Bridge Fellowship Award from the Robert H. Lurie Cancer Center (to T.N.D.P.).
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Bromodomain and extraterminal domain (BET) proteins, which are important epigenetic readers, are often dysregulated in cancer. While a number of BET inhibitors are currently in early phase clinical trials, BET inhibitors show limited single-agent activity. The purpose of this study is to determine if Quercetin, a naturally occurring polyphenolic flavonoid often found abundant in fruits and vegetables, can enhance the anti-tumor effects of BET inhibitors. The efficacy of the combination was evaluated in vitro and in a xenograft model of pancreatic cancer. Co-treatment with BET inhibitors and Quercetin promoted apoptosis, decreased sphere-forming ability by cancer cells, and decreased cell proliferation. We found that hnRNPA1, a nuclear protein known to control mRNA export and mRNA translation of anti-apoptotic proteins, mediates some anti-tumor effects by Quercetin. Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin. Significantly, Quercetin decreased hnRNPA1 in vivo and enhanced the effects of BET inhibitors at suppressing tumor growth. Together, these results demonstrate that Quercetin enhances the efficacy of BET inhibitors by suppressing hnRNPA1, and identify combination therapy with Quercetin and BET inhibitors for the treatment of cancer patients.
AB - Bromodomain and extraterminal domain (BET) proteins, which are important epigenetic readers, are often dysregulated in cancer. While a number of BET inhibitors are currently in early phase clinical trials, BET inhibitors show limited single-agent activity. The purpose of this study is to determine if Quercetin, a naturally occurring polyphenolic flavonoid often found abundant in fruits and vegetables, can enhance the anti-tumor effects of BET inhibitors. The efficacy of the combination was evaluated in vitro and in a xenograft model of pancreatic cancer. Co-treatment with BET inhibitors and Quercetin promoted apoptosis, decreased sphere-forming ability by cancer cells, and decreased cell proliferation. We found that hnRNPA1, a nuclear protein known to control mRNA export and mRNA translation of anti-apoptotic proteins, mediates some anti-tumor effects by Quercetin. Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin. Significantly, Quercetin decreased hnRNPA1 in vivo and enhanced the effects of BET inhibitors at suppressing tumor growth. Together, these results demonstrate that Quercetin enhances the efficacy of BET inhibitors by suppressing hnRNPA1, and identify combination therapy with Quercetin and BET inhibitors for the treatment of cancer patients.
KW - Bromodomain and extraterminal domain (BET) inhibitors
KW - Combination therapy
KW - Flavonoids
KW - Heterogeneous nuclear nucleoprotein A1 (hnRNPA1)
KW - Pancreatic cancer
KW - Quercetin
KW - Survivin
KW - Thyroid cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85071766876&partnerID=8YFLogxK
U2 - 10.3390/ijms20174293
DO - 10.3390/ijms20174293
M3 - Article
C2 - 31480735
AN - SCOPUS:85071766876
SN - 1661-6596
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 17
M1 - 4293
ER -
