Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells
Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells
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DOI：
10.1038/sj.onc.1210076
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发表时间：
2007-04-26
期刊：
影响因子：
8
通讯作者：
Schaefer, H.
中科院分区：
文献类型：
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作者：
Muerkoester, S. Sebens;Werbing, V.;Schaefer, H.
胰腺导管腺癌（PDAC）的特点是肿瘤进展迅速、转移潜能高以及对化疗药物具有高度耐药性。我们最近报道，通过长期化疗在胰腺导管腺癌细胞系PT45 - P1中诱导出的耐药表型涉及白细胞介素1β（IL1β）依赖性的一氧化氮（NO）分泌增加，这是有效抑制半胱天冬酶的原因。在本研究中，我们阐明了一种在其他恶性肿瘤中先前已发现的黏附分子L1CAM在这种依赖于NO的耐药性中的作用。耐药的PT45 - P1res细胞，而非对化疗敏感的亲本PT45 - P1细胞，以ILβ依赖的方式高水平表达L1CAM。经短干扰RNA（siRNA）介导的L1CAM敲低的PT45 - P1res细胞表现出诱导型一氧化氮合酶表达和NO分泌减少，以及抗癌药物诱导的半胱天冬酶活化显著增加，而NO供体S - 亚硝基 - N - 乙酰 - D,L - 青霉胺可逆转这种效应。相反，在PT45 - P1细胞中过表达L1CAM赋予其对抗癌药物治疗的抗凋亡保护作用。有趣的是，如在其他与L1CAM相关的活动中所报道的那样，例如通过ADAM10进行的L1CAM胞外域脱落，似乎对于L1CAM的抗凋亡保护作用并非必需。在表达L1CAM的耐药PT45 - P1细胞中既未检测到脱落的L1CAM胞外域，各种金属蛋白酶抑制剂的使用也不影响依赖于L1CAM的耐药性。免疫组织化学分析显示80%的胰腺癌标本中有L1CAM表达，支持L1CAM在该肿瘤恶性程度中的潜在作用。这些发现加深了我们对导致胰腺导管腺癌细胞耐药的分子机制的理解，并表明了L1CAM在这种情况下的重要性。
Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1b)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAMin an IL beta-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)- mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anticancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAMin PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for antiapoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAMin the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAMin this scenario.