Lung cancer and lung injury: the dual role of ceramide.
Lung cancer and lung injury: the dual role of ceramide.
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DOI：
10.1007/978-3-7091-1511-4_5
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发表时间：
2013
影响因子：
--
通讯作者：
Filosto, Simone
中科院分区：
文献类型：
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作者：
Goldkorn, Tzipora;Chung, Samuel;Filosto, Simone
鞘脂在癌症中起着关键作用，但我们目前对鞘脂在肺癌中的功能的了解仅限于少数关键参与者。其中最具特征的是鞘氨醇-1-磷酸盐和神经酰胺，它们被描述为在细胞命运中的相反作用。然而，由于鞘脂作为一个整体很容易相互转换的复杂的酶机制，没有单一的鞘脂似乎有确切的一个作用。相反，特定的鞘脂的作用似乎是特定的上下文，如研究结果所示，神经酰胺-1-磷酸具有增殖和凋亡作用，这取决于其浓度。因此，我们在此介绍了几年来对神经酰胺的研究，神经酰胺是一种与凋亡信号相关的鞘脂，它在癌症研究中因其在增殖和通过外泌体进行细胞间通讯中的潜在作用而出现。神经酰胺是一种在正常和病理条件下（从皮肤发育到肺癌）得到充分研究的鞘脂。有趣的是，几个研究小组以前曾报道过吸烟的肺气肿患者中其水平增加，吸烟的患者亚群非常容易患肺癌。然而，香烟烟雾（CS）和神经酰胺积聚导致肺癌，特别是非小细胞肺癌（NSCLC）的分子机制尚不清楚。有趣的是，最近的研究清楚地表明，两个信号通路被激活CS暴露在肺气道。一个中心是中性鞘磷脂酶2（nSMase 2）的激活，这是一种将鞘磷脂水解为神经酰胺的酶。另一个途径集中在致癌的EGF受体（EGFR），它变得异常激活，但不降解，导致延长增殖信号。最近的研究表明，这两个信号通路实际上可能会融合和整合。具体而言，Goldkorn等人证明，在CS暴露期间，EGFR有利地共定位于质膜的神经酰胺富集区域，这表明nSMase 2/神经酰胺在异常EGFR活化中发挥作用，导致致瘤信号增强。此外，新的研究结果表明，CS暴露可能诱导耐药的酪氨酸激酶抑制剂（TKI），用于治疗NSCLC，仅仅通过翻译后分子改变。此外，CS激活的EGFR的结构异常似乎得到了肺上皮细胞质膜中CS激活的nSMase 2产生的过量神经酰胺的支持。在本章中，我们以神经酰胺为例介绍了鞘脂领域在肺癌中的进展。然而，由于大量有希望的观察结果，有关鞘脂在肺癌中的作用的许多关键问题仍有待回答。
Sphingolipids play key roles in cancer, yet our current understanding of sphingolipid function in lung cancer is limited to a few key players. The best characterized of these are sphingosine-1-phoshate and ceramide which are described for their opposing roles in cell fate. However, because sphingolipids as a whole are readily interconverted by a complex enzymatic machinery, no single sphingolipid appears to have exactly one role. Instead, the roles of specific sphingolipids appear to be context specific as demonstrated by findings that ceramide-1-phosphate has both proliferative and apoptotic effects depending on its concentration. Therefore, we present herein several years of research on ceramide, a sphingolipid linked to apoptotic signaling, that is emerging in cancer research for its potential roles in proliferation and cell-to-cell communication via exosomes. Ceramide is a well-studied sphingolipid in both normal and pathological conditions ranging from skin development to lung cancer. Interestingly, several groups have previously reported its increased levels in emphysema patients who are smokers, a patient subpopulation greatly susceptible to lung cancer. However, the molecular mechanisms through which cigarette smoke (CS) and ceramide accumulation lead to lung cancer, non-small cell lung cancer (NSCLC) specifically, are unknown. Interestingly, recent studies clearly establish that two signaling pathways are activated during CS exposure in the lung airway. One centers on the activation of neutral sphingomyelinase2 (nSMase2), an enzyme that hydrolyzes sphingomyelin to ceramide. The other pathway focuses on the oncogenic EGF receptor (EGFR), which becomes aberrantly activated but not degraded, leading to prolonged proliferative signaling. Recent studies show that these two signaling pathways may actually converge and integrate. Specifically, Goldkorn et al. demonstrated that during CS exposure, EGFR is favorably co-localized in ceramide-enriched regions of the plasma membrane, proposing that nSMase2/ceramide plays a role in the aberrant EGFR activation, leading to augmented tumorigenic signaling. Moreover, new findings indicate that CS exposure may induce resistance to the tyrosine kinase inhibitors (TKIs), used for treatment of NSCLC, merely through posttranslational molecular alterations. Furthermore, structural anomalies of the CS-activated EGFR appear to be supported by the excess ceramide produced by the CS-activated nSMase2 in the plasma membrane of lung epithelial cells. We present in this chapter the progression of the sphingolipid field in lung cancer using ceramide as an example. However, many crucial questions remain to be answered regarding the role of sphingolipids in lung cancer because of the glut of promising observations.