In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer

Tse-Hung Huang, Alexander T H Wu, Tai-Shan Cheng, Kuan-Ting Lin, Chia-Jou Lai, Hao-Wen Hsieh, Peter Mu-Hsin Chang, Cheng-Wen Wu, Chi-Ying F Huang, Kuan-Yu Chen

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
JournalJournal of Cellular and Molecular Medicine
DOIs
Publication statusE-pub ahead of print - Oct 22 2019

Fingerprint

Thiostrepton
Neoplastic Stem Cells
Non-Small Cell Lung Carcinoma
Computer Simulation
Drug Therapy
Growth
gemcitabine
Neoplasms
Oligopeptides
Epithelial-Mesenchymal Transition
src-Family Kinases
Pharmaceutical Preparations
Genes
Cell Movement
Disease Progression

Cite this

In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer. / Huang, Tse-Hung; Wu, Alexander T H; Cheng, Tai-Shan; Lin, Kuan-Ting; Lai, Chia-Jou; Hsieh, Hao-Wen; Chang, Peter Mu-Hsin; Wu, Cheng-Wen; Huang, Chi-Ying F; Chen, Kuan-Yu.

In: Journal of Cellular and Molecular Medicine, 22.10.2019.

Research output: Contribution to journalArticle

Huang, Tse-Hung ; Wu, Alexander T H ; Cheng, Tai-Shan ; Lin, Kuan-Ting ; Lai, Chia-Jou ; Hsieh, Hao-Wen ; Chang, Peter Mu-Hsin ; Wu, Cheng-Wen ; Huang, Chi-Ying F ; Chen, Kuan-Yu. / In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer. In: Journal of Cellular and Molecular Medicine. 2019.
@article{41011369b6544e2fa4d6d2d94efb3ce1,
title = "In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer",
abstract = "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.",
author = "Tse-Hung Huang and Wu, {Alexander T H} and Tai-Shan Cheng and Kuan-Ting Lin and Chia-Jou Lai and Hao-Wen Hsieh and Chang, {Peter Mu-Hsin} and Cheng-Wen Wu and Huang, {Chi-Ying F} and Kuan-Yu Chen",
note = "{\circledC} 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.",
year = "2019",
month = "10",
day = "22",
doi = "10.1111/jcmm.14689",
language = "English",
journal = "Journal of Cellular and Molecular Medicine",
issn = "1582-1838",
publisher = "Wiley-Blackwell",

}

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 - © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

PY - 2019/10/22

Y1 - 2019/10/22

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.

U2 - 10.1111/jcmm.14689

DO - 10.1111/jcmm.14689

M3 - Article

C2 - 31638335

JO - Journal of Cellular and Molecular Medicine

JF - Journal of Cellular and Molecular Medicine

SN - 1582-1838

ER -