Lebedeva Irina V, Su Zao-Zhong, Sarkar Devanand, Kitada Shinichi, Dent Paul, Waxman Samuel, Reed John C, Fisher Paul B
Department of Pathology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Cancer Res. 2003 Dec 1;63(23):8138-44.
Mda-7/IL-24 (Ad.mda-7) is a novel cytokine gene belonging to the interleukin (IL) 10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 causes growth suppression and apoptosis in a wide spectrum of cancer cells, including prostate, without harming normal cells. We now demonstrate that Ad.mda-7 selectively induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and reactive oxygen species (ROS) production. Antioxidants (N-acetyl-L-cysteine and Tiron) and inhibitors of mitochondrial permeability transition (cyclosporine A and bongkrekic acid) inhibit Ad.mda-7-induced mitochondrial dysfunction and apoptosis. Conversely, agents augmenting ROS production (arsenic trioxide, NSC656240, and PK11195) facilitate Ad.mda-7-induced apoptosis. Ectopic expression of Bcl-2 and Bcl-x(L) inhibits mitochondrial changes, ROS production, and apoptosis providing additional support for an association between mitochondrial dysfunction and Ad.mda-7 action. These studies present definitive evidence that changes in mitochondrial function and ROS production are key components associated with selective killing of prostate cancer cells by mda-7/IL-24.
Mda-7/IL-24（腺病毒介导的mda-7）是一种属于白细胞介素（IL）10基因超家族的新型细胞因子基因。腺病毒介导的mda-7/IL-24递送可导致多种癌细胞（包括前列腺癌细胞）生长受抑制并发生凋亡，而不损害正常细胞。我们现在证明，腺病毒介导的mda-7通过促进线粒体功能障碍和活性氧（ROS）生成，选择性地诱导前列腺癌细胞凋亡。抗氧化剂（N-乙酰-L-半胱氨酸和钛铁试剂）和线粒体通透性转换抑制剂（环孢素A和膨压酸）可抑制腺病毒介导的mda-7诱导的线粒体功能障碍和凋亡。相反，增强ROS生成的试剂（三氧化二砷、NSC656240和PK11195）可促进腺病毒介导的mda-7诱导的凋亡。Bcl-2和Bcl-x(L)的异位表达可抑制线粒体变化、ROS生成和凋亡，为线粒体功能障碍与腺病毒介导的mda-7作用之间的关联提供了额外支持。这些研究提供了确凿证据，表明线粒体功能变化和ROS生成是与mda-7/IL-24选择性杀伤前列腺癌细胞相关的关键因素。
