PMID- 25391371
OWN - NLM
STAT- MEDLINE
DCOM- 20150727
LR  - 20190221
IS  - 1432-1335 (Electronic)
IS  - 0171-5216 (Linking)
VI  - 141
IP  - 6
DP  - 2015 Jun
TI  - Targeting FoxM1 by thiostrepton inhibits growth and induces apoptosis of 
      laryngeal squamous cell carcinoma.
PG  - 971-81
LID - 10.1007/s00432-014-1872-3 [doi]
AB  - PURPOSE: We have previously reported that forkhead box M1 (FoxM1) transcription 
      factor was overexpressed in laryngeal squamous cell carcinoma (LSCC) and was 
      associated with development of LSCC. However, there are limited studies regarding 
      the functional significance of FoxM1 and FoxM1 inhibitor thiostrepton in LSCC. 
      Therefore, the aim of this study was to examine both in vitro and in vivo 
      activity of FoxM1 inhibitor thiostrepton against LSCC cell line and nude mice. 
      METHODS: Cell viability was studied by CCK-8 assay. Cell growth was evaluated by 
      CFSE staining and cell cycle analysis. Apoptosis was measured by flow cytometry. 
      The mRNA and protein expression were detected by quantitative real-time RT-PCR, 
      Western blot and immunohistochemical staining. Xenograft model of tumor formation 
      was used to investigate how thiostrepton influences tumorigenesis in vivo. 
      RESULTS: Overexpression of FoxM1 in LSCC cells was down-regulated by thiostrepton 
      in a dose-dependent manner. Thiostrepton caused dose- and time-dependent 
      suppression of cell viability of LSCC. Moreover, thiostrepton induced cell cycle 
      arrest at S phase at early time and inhibited DNA synthesis in LSCC cells in a 
      dose- and time-dependent manner by down-regulation of cyclin D1 and cyclin E1. 
      Thiostrepton also induced dose- and time-dependent apoptosis of LSCC cells by 
      down-regulation of Bcl-2, up-regulation of Bax and p53, and inducing release of 
      cytochrome c accompanied by activation of cleaved caspase-9, cleaved caspase-3 
      and cleaved PARP. In addition, z-VAD-fmk, a universal inhibitor of caspases, 
      prevented activation of cleavage caspase-3 and abrogates cell death induced by 
      thiostrepton treatment. Furthermore, FADD and cleaved caspase-8 were activated, 
      and expression of cIAP1, XIAP and survivin were inhibited by thiostrepton. 
      Finally, treatment of LSCC cell line xenografts with thiostrepton resulted in 
      tumorigenesis inhibition of tumors in nude mice by reducing proliferation and 
      inducing apoptosis of LSCC cells. CONCLUSIONS: Collectively, our finding suggest 
      that targeting FoxM1 by thiostrepton inhibit growth and induce apoptosis of LSCC 
      through mitochondrial- and caspase-dependent intrinsic pathway and Fas-dependent 
      extrinsic pathway as well as IAP family. Thiostrepton may represent a novel lead 
      compound for targeted therapy of LSCC.
FAU - Jiang, Lizhu
AU  - Jiang L
AD  - Department of Otolaryngology, The First Affiliated Hospital of Chongqing Medical 
      University, 1 Youyi Rd, Chongqing, 400016, People's Republic of China.
FAU - Wu, Xiaosong
AU  - Wu X
FAU - Wang, Peng
AU  - Wang P
FAU - Wen, Taoyu
AU  - Wen T
FAU - Yu, Chao
AU  - Yu C
FAU - Wei, Lei
AU  - Wei L
FAU - Chen, Hongyan
AU  - Chen H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141113
PL  - Germany
TA  - J Cancer Res Clin Oncol
JT  - Journal of cancer research and clinical oncology
JID - 7902060
RN  - 0 (Antineoplastic Agents)
RN  - 0 (FOXM1 protein, human)
RN  - 0 (Forkhead Box Protein M1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - EC 3.4.22.- (Caspases)
RN  - HR4S203Y18 (Thiostrepton)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Blotting, Western
MH  - Carcinoma, Squamous Cell/*drug therapy/pathology
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/drug effects
MH  - Flow Cytometry
MH  - Forkhead Box Protein M1
MH  - Forkhead Transcription Factors/*antagonists & inhibitors/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Head and Neck Neoplasms/*drug therapy/pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Inhibitor of Apoptosis Proteins/metabolism
MH  - Laryngeal Neoplasms/*drug therapy/pathology
MH  - Mice
MH  - Mice, Nude
MH  - *Molecular Targeted Therapy/methods
MH  - Random Allocation
MH  - Real-Time Polymerase Chain Reaction
MH  - Signal Transduction
MH  - Squamous Cell Carcinoma of Head and Neck
MH  - Thiostrepton/administration & dosage/*pharmacology
MH  - Time Factors
MH  - Xenograft Model Antitumor Assays
EDAT- 2014/11/14 06:00
MHDA- 2015/07/28 06:00
CRDT- 2014/11/14 06:00
PHST- 2014/06/08 00:00 [received]
PHST- 2014/11/05 00:00 [accepted]
PHST- 2014/11/14 06:00 [entrez]
PHST- 2014/11/14 06:00 [pubmed]
PHST- 2015/07/28 06:00 [medline]
AID - 10.1007/s00432-014-1872-3 [doi]
PST - ppublish
SO  - J Cancer Res Clin Oncol. 2015 Jun;141(6):971-81. doi: 10.1007/s00432-014-1872-3. 
      Epub 2014 Nov 13.