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Antiviral Drug Ribavirin Targets Thyroid Cancer Cells by Inhibiting the eIF4E-β-Catenin Axis.

Abstract Although eukaryotic translation initiation factor 4E (eIF4E) is important in cancer development and progression, its role in thyroid cancer is not well understood. Ribavirin, an anti-viral drug, has been identified as an eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid cancer and its molecular mechanisms of action.
PMID
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Authors

Mayor MeshTerms
Keywords

Drug repurposing

Ribavirin

Thyroid cancer

eIF4E

β-catenin

Journal Title the american journal of the medical sciences
Publication Year Start




PMID- 28864377
OWN - NLM
STAT- MEDLINE
DA  - 20170902
DCOM- 20170908
LR  - 20170908
IS  - 1538-2990 (Electronic)
IS  - 0002-9629 (Linking)
VI  - 354
IP  - 2
DP  - 2017 Aug
TI  - Antiviral Drug Ribavirin Targets Thyroid Cancer Cells by Inhibiting the
      eIF4E-beta-Catenin Axis.
PG  - 182-189
LID - S0002-9629(17)30161-1 [pii]
LID - 10.1016/j.amjms.2017.03.025 [doi]
AB  - BACKGROUND: Although eukaryotic translation initiation factor 4E (eIF4E) is
      important in cancer development and progression, its role in thyroid cancer is
      not well understood. Ribavirin, an anti-viral drug, has been identified as an
      eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid
      cancer and its molecular mechanisms of action. MATERIALS AND METHODS: The effects
      of ribavirin on thyroid cancer was investigated using in vitro cellular assays
      and in vivo xenograft mouse model. The mechanism of its action on
      eIF4E-beta-catenin axis was examined using genetic and biochemical approaches.
      RESULTS: We show that ribavirin inhibited proliferation and induced apoptosis in 
      the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid
      cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid
      cancer's response to paclitaxel. Mechanistically, ribavirin suppressed eIF4E
      phosphorylation and overexpression of its wildtype and phosphor-mimetic form
      (S209D) but not of the non-phosphorylatable form (S209A), which rescued the
      inhibitory effects of ribavirin in thyroid cancer cells. We further demonstrated 
      that ribavirin suppressed phosphorylation and activities of beta-catenin and its 
      subsequent gene transcriptional expression. beta-Catenin overexpression rescued
      the effects of ribavirin in thyroid cancer cells. Importantly, we show that eIF4E
      regulated beta-catenin and that the regulation depended on phosphorylation at
      S209. The in vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and
      beta-catenin were also observed in thyroid tumor. CONCLUSIONS: Our data clearly
      demonstrate that ribavirin acts on thyroid cancer cells by inhibiting
      eIF4E/beta-catenin signaling. Our findings suggest that ribavirin has the
      potential to be repurposed for thyroid cancer treatment and also highlight the
      therapeutic value of inhibiting eIF4E-beta-catenin in thyroid cancer.
CI  - Copyright (c) 2017 Southern Society for Clinical Investigation. Published by
      Elsevier Inc. All rights reserved.
FAU - Shen, Xiawei
AU  - Shen X
AD  - Department of Endocrinology, The First Affiliated Hospital of Yangtze University,
      Jingzhou, Hubei Province, Peoples Republic of China.
FAU - Zhu, Yali
AU  - Zhu Y
AD  - Department of Endocrinology, The First Affiliated Hospital of Yangtze University,
      Jingzhou, Hubei Province, Peoples Republic of China.
FAU - Xiao, Zuixuan
AU  - Xiao Z
AD  - Department of Endocrinology, The First Affiliated Hospital of Yangtze University,
      Jingzhou, Hubei Province, Peoples Republic of China.
FAU - Dai, Xuemei
AU  - Dai X
AD  - Department of Endocrinology, The First Affiliated Hospital of Yangtze University,
      Jingzhou, Hubei Province, Peoples Republic of China.
FAU - Liu, Dan
AU  - Liu D
AD  - Department of Endocrinology, The First Affiliated Hospital of Yangtze University,
      Jingzhou, Hubei Province, Peoples Republic of China.
FAU - Li, Lin
AU  - Li L
AD  - Department of Endocrinology, The First Affiliated Hospital of Yangtze University,
      Jingzhou, Hubei Province, Peoples Republic of China.
FAU - Xiao, Baolai
AU  - Xiao B
AD  - Department of General Surgery, The First Affiliated Hospital of Yangtze
      University, Jingzhou, Hubei Province, Peoples Republic of China. Electronic
      address: [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170316
PL  - United States
TA  - Am J Med Sci
JT  - The American journal of the medical sciences
JID - 0370506
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Antiviral Agents)
RN  - 0 (beta Catenin)
RN  - 49717AWG6K (Ribavirin)
RN  - P88XT4IS4D (Paclitaxel)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use
MH  - Antiviral Agents/pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Mice
MH  - Mice, SCID
MH  - Paclitaxel/pharmacology
MH  - Ribavirin/*pharmacology/therapeutic use
MH  - Signal Transduction/*drug effects
MH  - Thyroid Neoplasms/*drug therapy
MH  - Xenograft Model Antitumor Assays
MH  - beta Catenin/metabolism
OTO - NOTNLM
OT  - Drug repurposing
OT  - Ribavirin
OT  - Thyroid cancer
OT  - eIF4E
OT  - beta-catenin
EDAT- 2017/09/03 06:00
MHDA- 2017/09/09 06:00
CRDT- 2017/09/03 06:00
PHST- 2017/01/17 [received]
PHST- 2017/03/13 [revised]
PHST- 2017/03/14 [accepted]
AID - S0002-9629(17)30161-1 [pii]
AID - 10.1016/j.amjms.2017.03.025 [doi]
PST - ppublish
SO  - Am J Med Sci. 2017 Aug;354(2):182-189. doi: 10.1016/j.amjms.2017.03.025. Epub
      2017 Mar 16.