IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
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DOI：
10.3390/cancers11121863
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发表时间：
2019-12-01
期刊：
影响因子：
5.2
通讯作者：
Judge, Andrew R.
中科院分区：
文献类型：
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作者：
Callaway, Chandler S.;Delitto, Andrea E.;Judge, Andrew R.
已知肿瘤源性细胞因子可驱动宿主组织的分解代谢，包括骨骼肌。然而，我们对启动这一过程的特定细胞因子的理解仍然不完整。在当前的研究中，我们对从人胰腺癌（PC）细胞、人肿瘤相关基质（TAS）细胞及其共培养的条件培养基（CM）中收集的细胞因子进行了多重分析分析。在确定的因素中，白细胞介素-8 （IL-8）从PC细胞和PC/TAS共培养中高水平释放，并且先前与癌症患者的低肌肉质量有关。因此，我们用IL-8处理C2C12肌管，导致ERK1/2、STAT和Smad信号的激活，并诱导肌管萎缩。此外，用IL-8治疗小鼠也引起了显著的肌肉萎缩，证实了IL-8对肌肉的体内相关性。机制上，用CXCR2拮抗剂SB225002或ERK1/2抑制剂U0126治疗可以抑制il -8诱导的肌管萎缩。我们进一步证明，这条轴介导了胰腺癌细胞CM诱导的肌肉萎缩，因为IL-8的中和或用SB225002或U0126治疗可显著抑制CM诱导的肌管萎缩。因此，这些数据支持从人PC细胞释放的IL-8通过CXCR2-ERK1/2启动肌肉细胞萎缩的关键作用。
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.