TY - JOUR
T1 - In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer
AU - Huang, Tse-Hung
AU - Wu, Alexander T H
AU - Cheng, Tai-Shan
AU - Lin, Kuan-Ting
AU - Lai, Chia-Jou
AU - Hsieh, Hao-Wen
AU - Chang, Peter Mu-Hsin
AU - Wu, Cheng-Wen
AU - Huang, Chi-Ying F
AU - Chen, Kuan-Yu
N1 - Funding Information:
This study was partially supported by grants from the Ministry of Science and Technology of Taiwan (MOST107‐2320‐B‐182A‐007‐) and Chang‐Gung Memorial Hospital Research Foundation (CMRPG2G0331 and CMRPG2G0332) to Tse‐Hung Huang, by grant from 102CM‐TMU‐03 to Alexander T. H. Wu, by grants from the Ministry of Science and Technology of Taiwan (MOST107‐2320‐B‐010‐040‐MY3), the Veterans General Hospitals and University System of Taiwan Joint Research Program (VGHUST108‐G1‐4‐1) and NYMU‐FEMH Joint Research Program (106DN20) to Chi‐Ying F. Huang, and by grants from the Ministry of Science and Technology of Taiwan (MOST106‐2314‐B‐002‐102‐MY3) to Kuan‐Yu Chen.
Publisher Copyright:
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti-CSC agent may lead to improved disease control. We used CSC-associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top-ranked candidate. In non-small-cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR-98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.
AB - Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti-CSC agent may lead to improved disease control. We used CSC-associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top-ranked candidate. In non-small-cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR-98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.
KW - cancer stem cell
KW - epithelial-to-mesenchymal transition
KW - miR-98
KW - non–small-cell lung cancer
KW - thiostrepton
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U2 - 10.1111/jcmm.14689
DO - 10.1111/jcmm.14689
M3 - Article
C2 - 31638335
SN - 1582-1838
VL - 23
SP - 8184
EP - 8195
JO - Journal of Cellular and Molecular Medicine
JF - Journal of Cellular and Molecular Medicine
IS - 12
ER -
