Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: An additional indirect anti-tumor effect of the drug

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Abstract

Context: Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial down-stream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors. Objective: This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines. Methods: Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours. Results: Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P <.0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P <.0001) but not in TPC-1 and BCPAP cell lines. Conclusion: Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug.

Original languageEnglish
Pages (from-to)E427-E432
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

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Metformin
Tumors
Thyroid Gland
Tumor Necrosis Factor-alpha
Cells
Thyroid Neoplasms
Pharmaceutical Preparations
Neoplasms
Analysis of variance (ANOVA)
Cell Line
Analysis of Variance
Neutrophil Infiltration
Animals
Animal Models
Neoplasm Metastasis
Phenotype
Survival
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

@article{8a210551d635444a9afc51bcce73a7d6,
title = "Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: An additional indirect anti-tumor effect of the drug",
abstract = "Context: Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial down-stream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors. Objective: This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines. Methods: Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours. Results: Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P <.0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P <.0001) but not in TPC-1 and BCPAP cell lines. Conclusion: Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug.",
author = "Mario Rotondi and Francesca Coperchini and Patrizia Pignatti and Flavia Magri and Luca Chiovato",
year = "2015",
month = "3",
day = "1",
doi = "10.1210/jc.2014-3045",
language = "English",
volume = "100",
pages = "E427--E432",
journal = "Journal of Clinical Endocrinology and Metabolism",
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publisher = "The Endocrine Society",
number = "3",

}

TY - JOUR

T1 - Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells

T2 - An additional indirect anti-tumor effect of the drug

AU - Rotondi, Mario

AU - Coperchini, Francesca

AU - Pignatti, Patrizia

AU - Magri, Flavia

AU - Chiovato, Luca

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Context: Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial down-stream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors. Objective: This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines. Methods: Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours. Results: Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P <.0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P <.0001) but not in TPC-1 and BCPAP cell lines. Conclusion: Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug.

AB - Context: Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial down-stream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors. Objective: This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines. Methods: Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours. Results: Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P <.0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P <.0001) but not in TPC-1 and BCPAP cell lines. Conclusion: Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug.

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U2 - 10.1210/jc.2014-3045

DO - 10.1210/jc.2014-3045

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VL - 100

SP - E427-E432

JO - Journal of Clinical Endocrinology and Metabolism

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