Chen Yuanbin, De Marco Melissa A, Graziani Irene, Gazdar Adi F, Strack Peter R, Miele Lucio, Bocchetta Maurizio
Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
Cancer Res. 2007 Sep 1;67(17):7954-9. doi: 10.1158/0008-5472.CAN-07-1229.
NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell fate during development and postnatal life. It has been increasingly linked to carcinogenesis, although its role in cancer seems to be highly context and tissue specific. Although NOTCH signaling is required for lung development, little is known about its role in lung cancer. In this study, we show that NOTCH signaling, as measured by the gamma-secretase cleavage product N(IC)-1, is active in both normal human and lung tumor samples; however, downstream NOTCH readouts (i.e., HES-1 and HES-5) are elevated in lung tumors. Levels of NOTCH signaling components in primary human lung cells reflect observations in tissue samples, yet lung tumor cell lines showed little NOTCH signaling. Because oxygen concentrations are important in normal lung physiology and lung tumors are hypoxic, the effect of low oxygen on these lung tumor cell lines was evaluated. We found that hypoxia dramatically elevates NOTCH signaling (especially NOTCH-1) in lung tumor cell lines and concomitantly sensitizes them to inhibition via small-molecule gamma-secretase inhibitors or NOTCH-1 RNA interference. gamma-Secretase inhibitor-induced apoptosis of lung tumor cells grown under hypoxic conditions could be rescued by reintroduction of active NOTCH-1. Our data strengthen the role of NOTCH in lung cancer and as a therapeutic target for the treatment of lung and other hypoxic tumor types.
NOTCH信号通路是一条在进化上保守的信号通路，在发育和出生后生活中调节细胞命运。它与肿瘤发生的联系日益紧密，尽管其在癌症中的作用似乎高度依赖背景和组织特异性。虽然NOTCH信号通路是肺发育所必需的，但其在肺癌中的作用却知之甚少。在本研究中，我们发现，通过γ-分泌酶切割产物N(IC)-1检测到的NOTCH信号通路在正常人类和肺肿瘤样本中均有活性；然而，下游NOTCH读数（即HES-1和HES-5）在肺肿瘤中升高。原代人肺细胞中NOTCH信号通路成分的水平反映了组织样本中的观察结果，但肺肿瘤细胞系中NOTCH信号通路活性较低。由于氧浓度在正常肺生理学中很重要，且肺肿瘤是缺氧的，因此评估了低氧对这些肺肿瘤细胞系的影响。我们发现，缺氧显著提高了肺肿瘤细胞系中的NOTCH信号通路（尤其是NOTCH-1），并同时使它们对小分子γ-分泌酶抑制剂或NOTCH-1 RNA干扰的抑制作用敏感。在缺氧条件下生长的肺肿瘤细胞中，γ-分泌酶抑制剂诱导的细胞凋亡可通过重新引入活性NOTCH-1来挽救。我们的数据强化了NOTCH在肺癌中的作用，并表明其可作为治疗肺癌和其他缺氧肿瘤类型的治疗靶点。
