Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1.
Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1.
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DOI：
10.1158/2159-8290.cd-12-0112
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发表时间：
2012-09
期刊：
影响因子：
28.2
通讯作者：
Heymach JV
中科院分区：
文献类型：
--
作者：
Byers LA;Wang J;Nilsson MB;Fujimoto J;Saintigny P;Yordy J;Giri U;Peyton M;Fan YH;Diao L;Masrorpour F;Shen L;Liu W;Duchemann B;Tumula P;Bhardwaj V;Welsh J;Weber S;Glisson BS;Kalhor N;Wistuba II;Girard L;Lippman SM;Mills GB;Coombes KR;Weinstein JN;Minna JD;Heymach JV
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，在转移潜能和治疗反应方面不同于非小细胞肺癌（NSCLC）。通过综合蛋白质组学和转录组学分析，我们研究了导致SCLC和NSCLC不同临床行为的分子差异。SCLC表现出几种受体酪氨酸激酶水平较低，PI3K和Ras/MEK通路的活化降低，但E2F1调节因子（包括EZH2、胸苷酸合成酶、凋亡介质和DNA修复蛋白）水平显著升高。此外，多聚（ADP - 核糖）聚合酶1（PARP1），一种DNA修复蛋白和E2F1共激活因子，在SCLC的mRNA和蛋白质水平上高度表达。PARP1和EZH2基因敲低可抑制SCLC的生长。此外，SCLC对PARP抑制剂比NSCLC敏感得多，并且PARP抑制可下调DNA修复机制的关键成分并提高化疗的疗效。
Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non-small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLC and NSCLC. SCLC demonstrated lower levels of several receptor tyrosine kinases and decreased activation of PI3K and Ras/MEK pathways, but significantly increased levels of E2F1-regulated factors including EZH2, thymidylate synthase, apoptosis mediators, and DNA repair proteins. Additionally, poly (ADP-ribose) polymerase 1 (PARP1), a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLC. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than NSCLC, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.