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IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy

Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium...

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Autores principales: Callaway, Chandler S., Delitto, Andrea E., D’Lugos, Andrew C., Patel, Rohan, Nosacka, Rachel L., Delitto, Daniel, Deyhle, Michael R., Trevino, Jose G., Judge, Sarah M., Judge, Andrew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966692/
https://www.ncbi.nlm.nih.gov/pubmed/31769424
http://dx.doi.org/10.3390/cancers11121863
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author Callaway, Chandler S.
Delitto, Andrea E.
D’Lugos, Andrew C.
Patel, Rohan
Nosacka, Rachel L.
Delitto, Daniel
Deyhle, Michael R.
Trevino, Jose G.
Judge, Sarah M.
Judge, Andrew R.
author_facet Callaway, Chandler S.
Delitto, Andrea E.
D’Lugos, Andrew C.
Patel, Rohan
Nosacka, Rachel L.
Delitto, Daniel
Deyhle, Michael R.
Trevino, Jose G.
Judge, Sarah M.
Judge, Andrew R.
author_sort Callaway, Chandler S.
collection PubMed
description Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2.
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spelling pubmed-69666922020-02-04 IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy Callaway, Chandler S. Delitto, Andrea E. D’Lugos, Andrew C. Patel, Rohan Nosacka, Rachel L. Delitto, Daniel Deyhle, Michael R. Trevino, Jose G. Judge, Sarah M. Judge, Andrew R. Cancers (Basel) Article Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2. MDPI 2019-11-25 /pmc/articles/PMC6966692/ /pubmed/31769424 http://dx.doi.org/10.3390/cancers11121863 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Callaway, Chandler S.
Delitto, Andrea E.
D’Lugos, Andrew C.
Patel, Rohan
Nosacka, Rachel L.
Delitto, Daniel
Deyhle, Michael R.
Trevino, Jose G.
Judge, Sarah M.
Judge, Andrew R.
IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
title IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
title_full IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
title_fullStr IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
title_full_unstemmed IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
title_short IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
title_sort il-8 released from human pancreatic cancer and tumor-associated stromal cells signals through a cxcr2-erk1/2 axis to induce muscle atrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966692/
https://www.ncbi.nlm.nih.gov/pubmed/31769424
http://dx.doi.org/10.3390/cancers11121863
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