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

Autor: Callaway CS; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., Delitto AE; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., Patel R; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., Nosacka RL; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., D'Lugos AC; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., Delitto D; Department of Surgery, University of Florida, Gainesville, FL 32610, USA., Deyhle MR; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., Trevino JG; Department of Surgery, University of Florida, Gainesville, FL 32610, USA., Judge SM; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA., Judge AR; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2019 Nov 25; Vol. 11 (12). Date of Electronic Publication: 2019 Nov 25.
DOI: 10.3390/cancers11121863
Abstrakt: 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.​.
Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Databáze: MEDLINE
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