Cargando…
Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer
Cancer stem cells (CSCs) are expanded in anaplastic thyroid cancer (ATC) and standard treatment approaches have failed to improve survival, suggesting a need to specifically target the CSC population. Recent studies in breast and colorectal cancer demonstrated that inhibition of the SUMO pathway rep...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777733/ https://www.ncbi.nlm.nih.gov/pubmed/29383121 http://dx.doi.org/10.18632/oncotarget.21954 |
_version_ | 1783294235542290432 |
---|---|
author | De Andrade, James P. Lorenzen, Allison W. Wu, Vincent T. Bogachek, Maria V. Park, Jung M. Gu, Vivian W. Sevenich, Claire M. Cassady, Victoria C. Beck, Anna C. Kulak, Mikhail V. Robinson, Robert A. Lal, Geeta Weigel, Ronald J. |
author_facet | De Andrade, James P. Lorenzen, Allison W. Wu, Vincent T. Bogachek, Maria V. Park, Jung M. Gu, Vivian W. Sevenich, Claire M. Cassady, Victoria C. Beck, Anna C. Kulak, Mikhail V. Robinson, Robert A. Lal, Geeta Weigel, Ronald J. |
author_sort | De Andrade, James P. |
collection | PubMed |
description | Cancer stem cells (CSCs) are expanded in anaplastic thyroid cancer (ATC) and standard treatment approaches have failed to improve survival, suggesting a need to specifically target the CSC population. Recent studies in breast and colorectal cancer demonstrated that inhibition of the SUMO pathway repressed CD44 and cleared the CSC population, mediated through SUMO-unconjugated TFAP2A. We sought to evaluate effects of inhibiting the SUMO pathway in ATC. ATC cell lines and primary ATC tumor samples were evaluated. The SUMO pathway was inhibited by knockdown of PIAS1 and use of SUMO inhibitors anacardic acid and PYR-41. The expression of TFAP2A in primary ATC was examined by immunohistochemistry. All ATC cell lines expressed TFAP2A but only 8505C expressed SUMO-conjugated TFAP2A. In 8505C only, inhibition of the SUMO pathway by knockdown of PIAS1 or treatment with SUMO inhibitors repressed expression of CD44 with a concomitant loss of SUMO-conjugated TFAP2A. The effect of SUMO inhibition on CD44 expression was dependent upon TFAP2A. Treatment with SUMO inhibitors resulted in a statistically improved tumor-free survival in mice harboring 8505C xenografts. An examination of primary ATC tissue determined that TFAP2A was expressed in 4 of 11 tumors surveyed. We conclude that inhibition of the SUMO pathway repressed the CSC population, delaying the outgrowth of tumor xenografts in ATC. The effect of SUMO inhibition was dependent upon expression of SUMO-conjugated TFAP2A, which may serve as a molecular marker for therapeutic effects of SUMO inhibitors. The findings provide pre-clinical evidence for development of SUMO inhibitors for the treatment of ATC. |
format | Online Article Text |
id | pubmed-5777733 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57777332018-01-30 Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer De Andrade, James P. Lorenzen, Allison W. Wu, Vincent T. Bogachek, Maria V. Park, Jung M. Gu, Vivian W. Sevenich, Claire M. Cassady, Victoria C. Beck, Anna C. Kulak, Mikhail V. Robinson, Robert A. Lal, Geeta Weigel, Ronald J. Oncotarget Research Paper Cancer stem cells (CSCs) are expanded in anaplastic thyroid cancer (ATC) and standard treatment approaches have failed to improve survival, suggesting a need to specifically target the CSC population. Recent studies in breast and colorectal cancer demonstrated that inhibition of the SUMO pathway repressed CD44 and cleared the CSC population, mediated through SUMO-unconjugated TFAP2A. We sought to evaluate effects of inhibiting the SUMO pathway in ATC. ATC cell lines and primary ATC tumor samples were evaluated. The SUMO pathway was inhibited by knockdown of PIAS1 and use of SUMO inhibitors anacardic acid and PYR-41. The expression of TFAP2A in primary ATC was examined by immunohistochemistry. All ATC cell lines expressed TFAP2A but only 8505C expressed SUMO-conjugated TFAP2A. In 8505C only, inhibition of the SUMO pathway by knockdown of PIAS1 or treatment with SUMO inhibitors repressed expression of CD44 with a concomitant loss of SUMO-conjugated TFAP2A. The effect of SUMO inhibition on CD44 expression was dependent upon TFAP2A. Treatment with SUMO inhibitors resulted in a statistically improved tumor-free survival in mice harboring 8505C xenografts. An examination of primary ATC tissue determined that TFAP2A was expressed in 4 of 11 tumors surveyed. We conclude that inhibition of the SUMO pathway repressed the CSC population, delaying the outgrowth of tumor xenografts in ATC. The effect of SUMO inhibition was dependent upon expression of SUMO-conjugated TFAP2A, which may serve as a molecular marker for therapeutic effects of SUMO inhibitors. The findings provide pre-clinical evidence for development of SUMO inhibitors for the treatment of ATC. Impact Journals LLC 2017-10-23 /pmc/articles/PMC5777733/ /pubmed/29383121 http://dx.doi.org/10.18632/oncotarget.21954 Text en Copyright: © 2017 De Andrade et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper De Andrade, James P. Lorenzen, Allison W. Wu, Vincent T. Bogachek, Maria V. Park, Jung M. Gu, Vivian W. Sevenich, Claire M. Cassady, Victoria C. Beck, Anna C. Kulak, Mikhail V. Robinson, Robert A. Lal, Geeta Weigel, Ronald J. Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer |
title | Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer |
title_full | Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer |
title_fullStr | Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer |
title_full_unstemmed | Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer |
title_short | Targeting the SUMO pathway as a novel treatment for anaplastic thyroid cancer |
title_sort | targeting the sumo pathway as a novel treatment for anaplastic thyroid cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777733/ https://www.ncbi.nlm.nih.gov/pubmed/29383121 http://dx.doi.org/10.18632/oncotarget.21954 |
work_keys_str_mv | AT deandradejamesp targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT lorenzenallisonw targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT wuvincentt targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT bogachekmariav targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT parkjungm targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT guvivianw targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT sevenichclairem targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT cassadyvictoriac targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT beckannac targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT kulakmikhailv targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT robinsonroberta targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT lalgeeta targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer AT weigelronaldj targetingthesumopathwayasanoveltreatmentforanaplasticthyroidcancer |