TY - JOUR
T1 - A novel YAP1 inhibitor targets CSC-enriched radiation-resistant cells and exerts strong antitumor activity in esophageal adenocarcinoma
AU - Song, Shumei
AU - Xie, Min
AU - Scott, Ailing W.
AU - Jin, Jiankang
AU - Ma, Lang
AU - Dong, Xiaochuan
AU - Skinner, Heath D.
AU - Johnson, Randy L.
AU - Ding, Sheng
AU - Ajani, Jaffer A.
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2018/2
Y1 - 2018/2
N2 - Mounting evidence suggests that the Hippo coactivator Yesassociated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma. However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on esophageal adenocarcinoma cell growth especially on YAP1 high-expressing esophageal adenocarcinoma cells both in vitro and in vivo. Remarkably, radiation-resistant cells acquire strong cancer stem cell (CSC) properties and aggressive phenotype, while CA3 can effectively suppress these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Furthermore, CA3, combined with 5-FU, synergistically inhibits esophageal adenocarcinoma cell growth especially in YAP1 high esophageal adenocarcinoma cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy-resistant esophageal adenocarcinoma cells endowed with CSC properties.
AB - Mounting evidence suggests that the Hippo coactivator Yesassociated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma. However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on esophageal adenocarcinoma cell growth especially on YAP1 high-expressing esophageal adenocarcinoma cells both in vitro and in vivo. Remarkably, radiation-resistant cells acquire strong cancer stem cell (CSC) properties and aggressive phenotype, while CA3 can effectively suppress these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Furthermore, CA3, combined with 5-FU, synergistically inhibits esophageal adenocarcinoma cell growth especially in YAP1 high esophageal adenocarcinoma cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy-resistant esophageal adenocarcinoma cells endowed with CSC properties.
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U2 - 10.1158/1535-7163.MCT-17-0560
DO - 10.1158/1535-7163.MCT-17-0560
M3 - Article
C2 - 29167315
AN - SCOPUS:85041463875
SN - 1535-7163
VL - 17
SP - 443
EP - 454
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -