Virology and Immunology Unit, GIGA-R, GIGA B34, University of Liège, Liège Belgium.
Biochem Pharmacol. 2011 Mar 1;81(5):606-16. doi: 10.1016/j.bcp.2010.12.015. Epub 2010 Dec 21.
Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are very resistant to all current therapies and are associated with a huge rate of recurrence. In most cases, this type of tumor is characterized by a constitutive activation of the nuclear factor-kappaB (NF-κB). This factor is known to be a key regulator of various physiological processes such as inflammation, immune response, cell growth or apoptosis. In the present study, we explored the role of NF-κB activation in the sensitivity of human glioblastoma cells to a treatment by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT). 5-ALA is a physiological compound widely used in PDT as well as in tumor photodetection (PDD). Our results show that inhibition of NF-κB improves glioblastoma cell death in response to 5-ALA-PDT. We then studied the molecular mechanisms underlying the cell death induced by PDT combined or not with NF-κB inhibition. We found that apoptosis was induced by PDT but in an incomplete manner and that, unexpectedly, NF-κB inhibition reduced its level. Oppositely PDT mainly induces necrosis in glioblastoma cells and NF-κB is found to have anti-necrotic functions in this context. The autophagic flux was also enhanced as a result of 5-ALA-PDT and we demonstrate that stimulation of autophagy acts as a pro-survival mechanism confering protection against PDT-mediated necrosis. These data point out that 5-ALA-PDT has an interesting potential as a mean to treat glioblastoma and that inhibition of NF-κB renders glioblastoma cells more sensitive to the treatment.
胶质母细胞瘤是最常见和最致命的星形细胞来源的脑肿瘤。它们对所有当前的治疗方法都具有很强的抵抗力，并且与极高的复发率相关。在大多数情况下，这种类型的肿瘤的特征是核因子-κB（NF-κB）的组成性激活。该因子已知是各种生理过程的关键调节剂，如炎症、免疫反应、细胞生长或细胞凋亡。在本研究中，我们探讨了 NF-κB 激活在人胶质母细胞瘤细胞对基于 5-氨基酮戊酸（5-ALA）的光动力疗法（PDT）治疗的敏感性中的作用。5-ALA 是一种生理化合物，广泛用于 PDT 以及肿瘤光检测（PDD）。我们的结果表明，抑制 NF-κB 可提高胶质母细胞瘤细胞对 5-ALA-PDT 的细胞死亡。然后，我们研究了与 NF-κB 抑制结合或不结合的 PDT 诱导细胞死亡的分子机制。我们发现 PDT 诱导了细胞凋亡，但不完全，出乎意料的是，NF-κB 抑制降低了其水平。相反，PDT 主要诱导胶质母细胞瘤细胞坏死，并且发现 NF-κB 在这种情况下具有抗坏死功能。自噬通量也因 5-ALA-PDT 而增强，我们证明自噬的刺激作为一种生存机制，赋予对 PDT 介导的坏死的保护作用。这些数据表明，5-ALA-PDT 作为治疗胶质母细胞瘤的一种有意义的手段具有很大的潜力，并且抑制 NF-κB 可使胶质母细胞瘤细胞对治疗更敏感。
