Cellular caspase-8-like inhibitory protein (cFLIP) prevents inhibition of muscle cell differentiation induced by cancer cells
Cellular caspase-8-like inhibitory protein (cFLIP) prevents inhibition of muscle cell differentiation induced by cancer cells
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DOI：
10.1096/fj.06-6347fje
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Clemens, Paula R.
中科院分区：
文献类型：
--
作者：
Jiang, Zhilong;Clemens, Paula R.
恶病质是癌症或其他慢性疾病的常见并发症。为了研究癌症恶病质的病理生理学并寻求治疗方案，我们开发了一种体外测定癌细胞产生的细胞因子对源自小鼠骨骼肌的原代肌细胞的影响的方法。这些研究导致了新的观察结果，即前列腺癌和黑色素瘤细胞系分泌的因子显著抑制原代小鼠肌肉细胞的分化。本研究中使用的癌细胞表达白细胞介素（IL）-1 β、TNF-α和蛋白水解诱导因子（PIF），表明它们在防止肌源性分化中的作用。在用癌细胞条件培养基或促炎细胞因子处理的肌细胞中，NF-κ B结合和转录活性均增强。IKBSR（一种已知的NF-κ B活化的阻遏物）和细胞半胱天冬酶-8样抑制蛋白（cFLIP）的稳定表达抑制了癌细胞培养基处理的肌细胞中NF-κ B的活化，伴随着肌源性蛋白表达和分化的增强。相反，抗凋亡蛋白Bcl-xL的过度表达并不能保护暴露于相同处理的成肌细胞。相反，我们观察到在Bcl-xL过表达细胞中NF-κ B的活化增强。这些研究表明，体外系统重现了导致肌肉恶病质的一些分子事件，并为新的治疗方法提供了基础。蒋志，克莱门斯，P. R.细胞半胱天冬酶-8样抑制蛋白（cFLIP）可防止癌细胞诱导的肌细胞分化抑制。
Cachexia is a frequent complication of cancer or other chronic diseases. To investigate the pathophysiology of cancer cachexia and pursue treatment options, we developed an in vitro assay of the effects of cancer cell-produced cytokines on primary muscle cells derived from murine skeletal muscle. These studies led to the novel observation that factors secreted by cell lines from prostate cancer and melanoma significantly inhibit differentiation of primary mouse muscle cells. The expression of interleukin (IL) -1 beta, TNF-alpha, and proteolysis-inducing factor (PIF) by cancer cells used in this study suggested their role in preventing myogenic differentiation. Both NF-kappa B binding and transcriptional activity were enhanced in muscle cells treated with conditioned media from cancer cells or with proinflammatory cytokines. Stable expression of IKBSR, a known repressor of NF-kappa B activation, and cellular caspase-8-like inhibitory protein (cFLIP) inhibited activation of NF-kappa B in cancer cell media-treated muscle cells with an accompanying enhancement of myogenic protein expression and differentiation. In contrast, overexpression of antiapoptotic protein Bcl-xL did not protect myoblast cells exposed to the same treatment. Instead, we observed enhanced activation of NF-kappa B in Bcl-xL overexpressing cells. These studies show that the in vitro system recapitulates some of the molecular events causing muscle cachexia and provides the basis for new treatment approaches.-Jiang, Z., Clemens, P. R. Cellular caspase-8-like inhibitory protein (cFLIP) prevents inhibition of muscle cell differentiation induced by cancer cells.