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Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer

Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of tri...

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Autores principales: McGinn, Olivia, Gupta, Vineet K., Dauer, Patricia, Arora, Nivedita, Sharma, Nikita, Nomura, Alice, Dudeja, Vikas, Saluja, Ashok, Banerjee, Sulagna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554238/
https://www.ncbi.nlm.nih.gov/pubmed/28801636
http://dx.doi.org/10.1038/s41598-017-08447-3
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author McGinn, Olivia
Gupta, Vineet K.
Dauer, Patricia
Arora, Nivedita
Sharma, Nikita
Nomura, Alice
Dudeja, Vikas
Saluja, Ashok
Banerjee, Sulagna
author_facet McGinn, Olivia
Gupta, Vineet K.
Dauer, Patricia
Arora, Nivedita
Sharma, Nikita
Nomura, Alice
Dudeja, Vikas
Saluja, Ashok
Banerjee, Sulagna
author_sort McGinn, Olivia
collection PubMed
description Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of triptolide (anti-cancer compound), decreases viability of cancer cells in vitro as well as in vivo. However, its mechanism of action remain elusive. In the current study we evaluated the effect of Minnelide, on hypoxia mediated oncogenic signaling as well as stemness in pancreatic cancer. Minnelide has just completed Phase 1 trial against GI cancers and is currently awaiting Phase 2 trials. Our results showed that upon treatment with triptolide, HIF-1α protein accumulated in pancreatic cancer cells even though hypoxic response was decreased in them. Our studies showed even though HIF-1α is accumulated in the treated cells, there was no decrease in HIF-1 binding to hypoxia response elements. However, the HIF-1 transcriptional activity was significantly reduced owing to depletion of co-activator p300 upon treatment with triptolide. Further, treatment with triptolide resulted in a decreased activity of Sp1 and NF-kB the two major oncogenic signaling pathway in pancreatic cancer along with a decreased tumor initiating cell (TIC) population in pancreatic tumor.
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spelling pubmed-55542382017-08-15 Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer McGinn, Olivia Gupta, Vineet K. Dauer, Patricia Arora, Nivedita Sharma, Nikita Nomura, Alice Dudeja, Vikas Saluja, Ashok Banerjee, Sulagna Sci Rep Article Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of triptolide (anti-cancer compound), decreases viability of cancer cells in vitro as well as in vivo. However, its mechanism of action remain elusive. In the current study we evaluated the effect of Minnelide, on hypoxia mediated oncogenic signaling as well as stemness in pancreatic cancer. Minnelide has just completed Phase 1 trial against GI cancers and is currently awaiting Phase 2 trials. Our results showed that upon treatment with triptolide, HIF-1α protein accumulated in pancreatic cancer cells even though hypoxic response was decreased in them. Our studies showed even though HIF-1α is accumulated in the treated cells, there was no decrease in HIF-1 binding to hypoxia response elements. However, the HIF-1 transcriptional activity was significantly reduced owing to depletion of co-activator p300 upon treatment with triptolide. Further, treatment with triptolide resulted in a decreased activity of Sp1 and NF-kB the two major oncogenic signaling pathway in pancreatic cancer along with a decreased tumor initiating cell (TIC) population in pancreatic tumor. Nature Publishing Group UK 2017-08-11 /pmc/articles/PMC5554238/ /pubmed/28801636 http://dx.doi.org/10.1038/s41598-017-08447-3 Text en © The Author(s) 2017 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
McGinn, Olivia
Gupta, Vineet K.
Dauer, Patricia
Arora, Nivedita
Sharma, Nikita
Nomura, Alice
Dudeja, Vikas
Saluja, Ashok
Banerjee, Sulagna
Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer
title Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer
title_full Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer
title_fullStr Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer
title_full_unstemmed Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer
title_short Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer
title_sort inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of hif1 transcription complex in pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554238/
https://www.ncbi.nlm.nih.gov/pubmed/28801636
http://dx.doi.org/10.1038/s41598-017-08447-3
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