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SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia

High fat diet leads to obesity, chronic inflammation, accelerated prostate cancer progression, and decreased survival. INPP4B, a dual specificity phosphatase, is a tumor suppressor which opposes Akt and PKC signaling pathways activated in response to obesity and prostate cancer progression. Previous...

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Autores principales: Zhang, Manqi, Vasquez, Judy, Kaftanovskaya, Elena, Agoulnik, Alexander, Vacher, Jean, Ittmann, Michael, Agoulnik, Irina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552162/
http://dx.doi.org/10.1210/js.2019-SAT-326
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author Zhang, Manqi
Vasquez, Judy
Kaftanovskaya, Elena
Agoulnik, Alexander
Vacher, Jean
Ittmann, Michael
Agoulnik, Irina
author_facet Zhang, Manqi
Vasquez, Judy
Kaftanovskaya, Elena
Agoulnik, Alexander
Vacher, Jean
Ittmann, Michael
Agoulnik, Irina
author_sort Zhang, Manqi
collection PubMed
description High fat diet leads to obesity, chronic inflammation, accelerated prostate cancer progression, and decreased survival. INPP4B, a dual specificity phosphatase, is a tumor suppressor which opposes Akt and PKC signaling pathways activated in response to obesity and prostate cancer progression. Previous research demonstrated that overexpression of PKC in mouse prostate leads to prostate intraepithelial neoplasia (PIN). Akt pathway stimulates prostate cancer progression in mice and is activated in all advanced prostate cancers in men. Using INPP4B knockout mouse model we tested whether INPP4B regulates prostate physiology in mice on high fat diet. The WT and Inpp4b(-/-) male mice were fed a low-fat diet (LFD) (11% fat) or high-fat diet (HFD) (58% fat) for 12 weeks. The mouse prostate was dissected into the anterior prostate (AP), dorsolateral prostate (DLP) and ventral prostate (VP). We observed that INPP4B and androgen receptor (AR) were expressed primarily in DLP and VP. INPP4B expression was decreased in the DLP of HFD fed mice. In the prostate of mice fed a LFD, we observed similar histological architecture in both WT and Inpp4b(-/-) mice. All the Inpp4b(-/-) mice fed a HFD developed PIN, whereas WT mice did not. Cells with polymorphic nuclei were abundant in PIN loci. The staining of α-SMA indicated that prostate epithelial cells invaded the stroma of HFD Inpp4b(-/-) mice. Consistent with the previous findings, HFD activated PKC, and the loss of INPP4B increased the levels of phospho-PKC βII and ζ in HFD mouse DLP. We previously reported that INPP4B loss changes AR transcriptional output in prostate cancer cells and normal mouse prostate. In HFD group, loss of INPP4B did not affect the level of AR in any of the three prostate lobes but led to an altered AR-dependent transcriptional activity. We show that the pro-inflammatory cytokines Il6, Tnfα and Il1β are expressed at low or undetectable levels in prostates of mice fed LFD. However, all three mediators were strikingly elevated in DLP of HFD Inpp4b(-/-) mice, where most of the PIN was also observed. Using an IL6 ELISA, we confirmed increases of IL6 protein levels in the prostates of the Inpp4b(-/-) HFD group. Consistent with elevated levels of inflammatory cytokines in prostates of Inpp4b(-/-) mice we detected an increase of macrophage specific biomarkers in the DLP of HFD groups, indicating HFD promotes macrophage infiltration in both WT and Inpp4b(-/-) mice. Importantly, no changes in PTEN were detected at both RNA and protein levels in Inpp4b(-/-) mice, indicating that increased inflammation and PIN development is due to the loss of INPP4B. Our data suggests that INPP4B suppresses oncogenic signaling pathways and opposes inflammation and neoplastic transformation in prostates of mice maintained on a high fat diet.
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spelling pubmed-65521622019-06-13 SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia Zhang, Manqi Vasquez, Judy Kaftanovskaya, Elena Agoulnik, Alexander Vacher, Jean Ittmann, Michael Agoulnik, Irina J Endocr Soc Tumor Biology High fat diet leads to obesity, chronic inflammation, accelerated prostate cancer progression, and decreased survival. INPP4B, a dual specificity phosphatase, is a tumor suppressor which opposes Akt and PKC signaling pathways activated in response to obesity and prostate cancer progression. Previous research demonstrated that overexpression of PKC in mouse prostate leads to prostate intraepithelial neoplasia (PIN). Akt pathway stimulates prostate cancer progression in mice and is activated in all advanced prostate cancers in men. Using INPP4B knockout mouse model we tested whether INPP4B regulates prostate physiology in mice on high fat diet. The WT and Inpp4b(-/-) male mice were fed a low-fat diet (LFD) (11% fat) or high-fat diet (HFD) (58% fat) for 12 weeks. The mouse prostate was dissected into the anterior prostate (AP), dorsolateral prostate (DLP) and ventral prostate (VP). We observed that INPP4B and androgen receptor (AR) were expressed primarily in DLP and VP. INPP4B expression was decreased in the DLP of HFD fed mice. In the prostate of mice fed a LFD, we observed similar histological architecture in both WT and Inpp4b(-/-) mice. All the Inpp4b(-/-) mice fed a HFD developed PIN, whereas WT mice did not. Cells with polymorphic nuclei were abundant in PIN loci. The staining of α-SMA indicated that prostate epithelial cells invaded the stroma of HFD Inpp4b(-/-) mice. Consistent with the previous findings, HFD activated PKC, and the loss of INPP4B increased the levels of phospho-PKC βII and ζ in HFD mouse DLP. We previously reported that INPP4B loss changes AR transcriptional output in prostate cancer cells and normal mouse prostate. In HFD group, loss of INPP4B did not affect the level of AR in any of the three prostate lobes but led to an altered AR-dependent transcriptional activity. We show that the pro-inflammatory cytokines Il6, Tnfα and Il1β are expressed at low or undetectable levels in prostates of mice fed LFD. However, all three mediators were strikingly elevated in DLP of HFD Inpp4b(-/-) mice, where most of the PIN was also observed. Using an IL6 ELISA, we confirmed increases of IL6 protein levels in the prostates of the Inpp4b(-/-) HFD group. Consistent with elevated levels of inflammatory cytokines in prostates of Inpp4b(-/-) mice we detected an increase of macrophage specific biomarkers in the DLP of HFD groups, indicating HFD promotes macrophage infiltration in both WT and Inpp4b(-/-) mice. Importantly, no changes in PTEN were detected at both RNA and protein levels in Inpp4b(-/-) mice, indicating that increased inflammation and PIN development is due to the loss of INPP4B. Our data suggests that INPP4B suppresses oncogenic signaling pathways and opposes inflammation and neoplastic transformation in prostates of mice maintained on a high fat diet. Endocrine Society 2019-04-30 /pmc/articles/PMC6552162/ http://dx.doi.org/10.1210/js.2019-SAT-326 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Tumor Biology
Zhang, Manqi
Vasquez, Judy
Kaftanovskaya, Elena
Agoulnik, Alexander
Vacher, Jean
Ittmann, Michael
Agoulnik, Irina
SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia
title SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia
title_full SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia
title_fullStr SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia
title_full_unstemmed SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia
title_short SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia
title_sort sat-326 inpp4b suppresses prostate inflammation and protects mice fed with high-fat diet from the development of prostate intraepithelial neoplasia
topic Tumor Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552162/
http://dx.doi.org/10.1210/js.2019-SAT-326
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