TY - JOUR
T1 - Inhibition of TACC3 by a small molecule inhibitor in breast cancer
AU - Campo, Loredana
AU - Breuer, Eun Kyoung
N1 - Funding Information:
This study was supported by Program Development Startup from Loyola University Chicago .
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.
AB - Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.
KW - Cancer cell stemness
KW - EMT
KW - KHS101
KW - Quantitative multiplexed proteomic analysis
KW - TACC3
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U2 - 10.1016/j.bbrc.2018.03.125
DO - 10.1016/j.bbrc.2018.03.125
M3 - Article
C2 - 29555478
AN - SCOPUS:85044129680
SN - 0006-291X
VL - 498
SP - 1085
EP - 1092
JO - Biochemical and biophysical research communications
JF - Biochemical and biophysical research communications
IS - 4
ER -