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Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers
PTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110β becomes the prominent PI3K isoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637061/ https://www.ncbi.nlm.nih.gov/pubmed/37706278 http://dx.doi.org/10.1111/cas.15960 |
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author | Kaysudu, Irmak Gungul, Taha Bugra Atici, Sena Yilmaz, Sevval Bayram, Engin Guven, Gozde Cizmecioglu, Nihal Terzi Sahin, Ozgur Yesiloz, Gurkan Haznedaroglu, Berat Zeki Cizmecioglu, Onur |
author_facet | Kaysudu, Irmak Gungul, Taha Bugra Atici, Sena Yilmaz, Sevval Bayram, Engin Guven, Gozde Cizmecioglu, Nihal Terzi Sahin, Ozgur Yesiloz, Gurkan Haznedaroglu, Berat Zeki Cizmecioglu, Onur |
author_sort | Kaysudu, Irmak |
collection | PubMed |
description | PTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110β becomes the prominent PI3K isoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using online bioinformatical tools, we examined two publicly available microarray datasets with aberrant PI3K activation. We found that the rate‐limiting enzyme of cholesterol biogenesis, SQLE, was significantly upregulated in p110β‐hyperactivated or PTEN‐deficient mouse prostate tumors. Concomitantly, the expression of cholesterol biosynthesis pathway enzymes was directly correlated with PI3K activation status in microarray datasets and diminished upon PTEN re‐expression in PTEN‐null prostate cancer cells. Particularly, PTEN re‐expression decreased SQLE protein levels in PTEN‐deficient prostate cancer cells. We performed targeted metabolomics and detected reduced levels of cholesteryl esters as well as free cholesterol upon PTEN re‐expression. Notably, PTEN‐null prostate and breast cancer cell lines were more sensitive to pharmacological intervention with the cholesterol pathway than PTEN‐replete cancer cells. Since steroid hormones use sterols as structural precursors, we studied whether cholesterol biosynthesis may be a metabolic vulnerability that enhances antihormone therapy in PTEN‐null castration‐resistant prostate cancer cells. Coinhibition of cholesterol biosynthesis and the androgen receptor enhanced their sensitivity. Moreover, PTEN suppression in endocrine therapy‐resistant luminal‐A breast cancer cells leads to an increase in SQLE expression and a corresponding sensitization to the inhibition of cholesterol synthesis. According to our data, targeting cholesterol biosynthesis in combination with the hormone receptor signaling axis can potentially treat hormone‐resistant prostate and breast cancers. |
format | Online Article Text |
id | pubmed-10637061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106370612023-11-15 Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers Kaysudu, Irmak Gungul, Taha Bugra Atici, Sena Yilmaz, Sevval Bayram, Engin Guven, Gozde Cizmecioglu, Nihal Terzi Sahin, Ozgur Yesiloz, Gurkan Haznedaroglu, Berat Zeki Cizmecioglu, Onur Cancer Sci ORIGINAL ARTICLES PTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110β becomes the prominent PI3K isoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using online bioinformatical tools, we examined two publicly available microarray datasets with aberrant PI3K activation. We found that the rate‐limiting enzyme of cholesterol biogenesis, SQLE, was significantly upregulated in p110β‐hyperactivated or PTEN‐deficient mouse prostate tumors. Concomitantly, the expression of cholesterol biosynthesis pathway enzymes was directly correlated with PI3K activation status in microarray datasets and diminished upon PTEN re‐expression in PTEN‐null prostate cancer cells. Particularly, PTEN re‐expression decreased SQLE protein levels in PTEN‐deficient prostate cancer cells. We performed targeted metabolomics and detected reduced levels of cholesteryl esters as well as free cholesterol upon PTEN re‐expression. Notably, PTEN‐null prostate and breast cancer cell lines were more sensitive to pharmacological intervention with the cholesterol pathway than PTEN‐replete cancer cells. Since steroid hormones use sterols as structural precursors, we studied whether cholesterol biosynthesis may be a metabolic vulnerability that enhances antihormone therapy in PTEN‐null castration‐resistant prostate cancer cells. Coinhibition of cholesterol biosynthesis and the androgen receptor enhanced their sensitivity. Moreover, PTEN suppression in endocrine therapy‐resistant luminal‐A breast cancer cells leads to an increase in SQLE expression and a corresponding sensitization to the inhibition of cholesterol synthesis. According to our data, targeting cholesterol biosynthesis in combination with the hormone receptor signaling axis can potentially treat hormone‐resistant prostate and breast cancers. John Wiley and Sons Inc. 2023-09-14 /pmc/articles/PMC10637061/ /pubmed/37706278 http://dx.doi.org/10.1111/cas.15960 Text en © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | ORIGINAL ARTICLES Kaysudu, Irmak Gungul, Taha Bugra Atici, Sena Yilmaz, Sevval Bayram, Engin Guven, Gozde Cizmecioglu, Nihal Terzi Sahin, Ozgur Yesiloz, Gurkan Haznedaroglu, Berat Zeki Cizmecioglu, Onur Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
title | Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
title_full | Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
title_fullStr | Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
title_full_unstemmed | Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
title_short | Cholesterol biogenesis is a PTEN‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
title_sort | cholesterol biogenesis is a pten‐dependent actionable node for the treatment of endocrine therapy‐refractory cancers |
topic | ORIGINAL ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637061/ https://www.ncbi.nlm.nih.gov/pubmed/37706278 http://dx.doi.org/10.1111/cas.15960 |
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