Cargando…

ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase

BACKGROUND: Mannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive. METHODS: MTT, colony formation and flow cyt...

Descripción completa

Detalles Bibliográficos
Autores principales: Ma, Sharui, Wang, Na, Liu, Rui, Zhang, Rui, Dang, Hui, Wang, Yubo, Wang, Simeng, Zeng, Zekun, Ji, Meiju, Hou, Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656095/
https://www.ncbi.nlm.nih.gov/pubmed/34886901
http://dx.doi.org/10.1186/s13046-021-02195-z
_version_ 1784612212609908736
author Ma, Sharui
Wang, Na
Liu, Rui
Zhang, Rui
Dang, Hui
Wang, Yubo
Wang, Simeng
Zeng, Zekun
Ji, Meiju
Hou, Peng
author_facet Ma, Sharui
Wang, Na
Liu, Rui
Zhang, Rui
Dang, Hui
Wang, Yubo
Wang, Simeng
Zeng, Zekun
Ji, Meiju
Hou, Peng
author_sort Ma, Sharui
collection PubMed
description BACKGROUND: Mannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive. METHODS: MTT, colony formation and flow cytometry assays were performed to determine the response of thyroid cancer cells to mannose. Meanwhile, mouse models of subcutaneous xenograft and primary papillary thyroid cancer were established to determine in vivo anti-tumor activity of mannose. The underlying mechanism of mannose selectively killing thyroid cancer cells was clarified by a series of molecular and biochemical experiments. RESULTS: Our data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn(2+)) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn(2+) supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn(2+) from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn(2+) concentration and enzyme activity of PMI. Moreover, ectopic expression of ZIP10 in mannose-sensitive cells decrease their cellular response to mannose. Mechanistically, mannose exerted its anti-tumor effect by inhibiting cellular glycolysis; however, this effect was highly dependent on expression status of ZIP10. CONCLUSION: The present study demonstrate that mannose selectively kills thyroid cancer cells dependent on enzyme activity of PMI rather than its expression, and provide a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02195-z.
format Online
Article
Text
id pubmed-8656095
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-86560952021-12-10 ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase Ma, Sharui Wang, Na Liu, Rui Zhang, Rui Dang, Hui Wang, Yubo Wang, Simeng Zeng, Zekun Ji, Meiju Hou, Peng J Exp Clin Cancer Res Research BACKGROUND: Mannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive. METHODS: MTT, colony formation and flow cytometry assays were performed to determine the response of thyroid cancer cells to mannose. Meanwhile, mouse models of subcutaneous xenograft and primary papillary thyroid cancer were established to determine in vivo anti-tumor activity of mannose. The underlying mechanism of mannose selectively killing thyroid cancer cells was clarified by a series of molecular and biochemical experiments. RESULTS: Our data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn(2+)) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn(2+) supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn(2+) from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn(2+) concentration and enzyme activity of PMI. Moreover, ectopic expression of ZIP10 in mannose-sensitive cells decrease their cellular response to mannose. Mechanistically, mannose exerted its anti-tumor effect by inhibiting cellular glycolysis; however, this effect was highly dependent on expression status of ZIP10. CONCLUSION: The present study demonstrate that mannose selectively kills thyroid cancer cells dependent on enzyme activity of PMI rather than its expression, and provide a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-021-02195-z. BioMed Central 2021-12-09 /pmc/articles/PMC8656095/ /pubmed/34886901 http://dx.doi.org/10.1186/s13046-021-02195-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Ma, Sharui
Wang, Na
Liu, Rui
Zhang, Rui
Dang, Hui
Wang, Yubo
Wang, Simeng
Zeng, Zekun
Ji, Meiju
Hou, Peng
ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
title ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
title_full ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
title_fullStr ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
title_full_unstemmed ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
title_short ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
title_sort zip10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656095/
https://www.ncbi.nlm.nih.gov/pubmed/34886901
http://dx.doi.org/10.1186/s13046-021-02195-z
work_keys_str_mv AT masharui zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT wangna zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT liurui zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT zhangrui zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT danghui zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT wangyubo zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT wangsimeng zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT zengzekun zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT jimeiju zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase
AT houpeng zip10isanegativedeterminantforantitumoreffectofmannoseinthyroidcancerbyactivatingphosphatemannoseisomerase