Mohr A, Büneker C, Gough R P, Zwacka R M
National Centre for Biomedical Engineering Science, Molecular Therapeutics Group, National University of Ireland Galway, Galway, Ireland.
Oncogene. 2008 Jan 31;27(6):763-74. doi: 10.1038/sj.onc.1210673. Epub 2007 Jul 23.
The mitochondrial enzyme manganese superoxide dismutase (MnSOD) has been shown to have two faces with regard to its role in tumor development. On the one side, it is well documented that overexpression of MnSOD slows down cancer cell growth, whereas on the other side MnSOD also has a metastasis-promoting activity. We set out to examine the role of MnSOD in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, thought to be a first-line tumor surveillance mechanism and failure to undergo apoptosis might contribute to metastasis formation. We show that overexpression of MnSOD at moderate levels is able to protect cells from TRAIL-induced apoptosis. While caspase-8 activation and Bid cleavage were not affected by MnSOD, we detected a marked decrease in caspase-3 activation pointing to a mitochondrial resistance mechanism. Indeed, we found that MnSOD-overexpressing cells showed reduced cytochrome c and no Smac/DIABLO release into the cytosol. The resulting lack of X-linked inhibitor of apoptosis (XIAP) inhibition by cytosolic Smac/DIABLO most likely caused the TRAIL resistance as RNAi against XIAP-rescued caspase-3 activity and TRAIL sensitivity. Our results show that reactive oxygen species are involved in TRAIL-induced Smac/DIABLO release and in TRAIL-triggered apoptosis. Hence, high levels of MnSOD, which decompose and neutralize these reactive oxygen species, might contribute to metastasis formation by allowing disseminated tumor cells to escape from TRAIL-mediated tumor surveillance. As part of TRAIL regimens, adjuvant treatment with XIAP inhibitors in the form of Smac/DIABLO mimetics or MnSOD inhibitors might be able to break TRAIL resistance of malignant tumor cells.
线粒体酶锰超氧化物歧化酶（MnSOD）在肿瘤发展中的作用已显示出两面性。一方面，有充分的文献记载，MnSOD的过表达会减缓癌细胞的生长，而另一方面，MnSOD也具有促进转移的活性。我们着手研究MnSOD在肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡中的作用，TRAIL诱导的凋亡被认为是一种一线肿瘤监测机制，而未能发生凋亡可能有助于转移的形成。我们发现，适度水平的MnSOD过表达能够保护细胞免受TRAIL诱导的凋亡。虽然半胱天冬酶-8的激活和Bid的切割不受MnSOD的影响，但我们检测到半胱天冬酶-3的激活明显降低，这表明存在一种线粒体抵抗机制。事实上，我们发现过表达MnSOD的细胞中细胞色素c减少，且没有Smac/DIABLO释放到细胞质中。细胞质中的Smac/DIABLO缺乏对凋亡抑制蛋白X连锁抑制因子（XIAP）的抑制作用，很可能导致了TRAIL抵抗，因为针对XIAP的RNA干扰恢复了半胱天冬酶-3的活性和TRAIL敏感性。我们的结果表明，活性氧参与了TRAIL诱导的Smac/DIABLO释放和TRAIL触发的凋亡。因此，高水平的MnSOD分解并中和这些活性氧，可能通过使播散的肿瘤细胞逃避TRAIL介导的肿瘤监测而促进转移的形成。作为TRAIL治疗方案的一部分，以Smac/DIABLO模拟物或MnSOD抑制剂形式使用XIAP抑制剂进行辅助治疗，可能能够打破恶性肿瘤细胞对TRAIL的抵抗。
