Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC)
Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC)
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DOI：
10.1038/sj.onc.1208333
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发表时间：
2005-02-17
期刊：
影响因子：
8
通讯作者：
Nemenoff, RA
中科院分区：
文献类型：
--
作者：
Bren-Mattison, Y;Van Putten, V;Nemenoff, RA
过氧化物酶体增殖物激活受体-γ（PPARgamma）的药理学激活剂已被证明主要通过生长抑制和诱导细胞凋亡来抑制肺肿瘤的生长。然而，由于这些药物中的许多涉及其他效应物，因此PPARgamma在肺肿瘤发生中的作用仍然不清楚。为了特异性地检查PPARgamma介导的事件，建立了过表达PPARgamma的非小细胞肺癌（NSCLC）细胞。与空载体转染的细胞（H2122-LNCX）相比，在H2122腺癌细胞中过表达PPARgamma（H2122-PPARgamma）阻断了锚定非依赖性生长，但在标准组织培养条件下对细胞增殖或凋亡没有显著影响。与H2122-LNCX细胞相比，H2122-PPARgamma细胞原位植入裸鼠肺中抑制了体内肿瘤生长和转移，并延长了存活期。与这些发现一致，如在Transwell测定中评估的，H2122-PPARgamma细胞具有受损的侵袭性。在三维培养系统中，H2122-PPARgamma细胞形成了与正常肺上皮细胞相似的极化球体结构。H2122-LNCX细胞形成非极化聚集体结构，并没有显示出任何这些上皮特性。这些数据表明，PPARgamma对肺肿瘤发生的抑制作用涉及选择性抑制侵袭性转移，以及激活促进更分化的上皮表型的途径。
Pharmacological activators of peroxisome proliferatoractivated receptor-gamma (PPARgamma) have been shown to inhibit growth of lung tumors largely through growth inhibition and induction of apopotosis. However, since many of these agents engage other effectors, the role of PPARgamma in lung tumorigenesis remains poorly defined. To specifically examine PPARgamma-mediated events, non-small-cell lung cancer (NSCLC) cells overexpressing PPARgamma were established. Overexpression of PPARgamma in H2122 adenocarcinoma cells (H2122-PPARgamma) blocked anchorage-independent growth compared to cells transfected with empty vector (H2122-LNCX), but had no significant effect on cell proliferation or apoptosis under standard tissue culture conditions. Orthotopic implantation of H2122-PPARgamma cells into the lungs of nude rats inhibited tumor growth and metastasis in vivo and prolonged survival compared to implantation of H2122-LNCX cells. Consistent with these findings, H2122-PPARgamma cells had an impaired invasiveness as assessed in Transwell assays. In a three-dimensional culture system, H2122-PPARgamma cells formed polarized spheroid structures similar to those observed with normal lung epithelial cells. H2122-LNCX cells formed nonpolarized aggregate structures and did not show any of these epithelial properties. These data indicate that inhibitory effects of PPARgamma on lung tumorigenesis involve selective inhibition of invasive metastasis, and activation of pathways that promote a more differentiated epithelial phenotype.