Venkataraman Sujatha, Jiang Xiaohong, Weydert Christine, Zhang Yuping, Zhang Hannah J, Goswami Prabhat C, Ritchie Justine M, Oberley Larry W, Buettner Garry R
Free Radical and Radiation Biology Program -- ESR Facility, University of Iowa, Iowa City, IA 52242-1101, USA.
Oncogene. 2005 Jan 6;24(1):77-89. doi: 10.1038/sj.onc.1208145.
This study investigates the role of the antioxidant enzyme manganese superoxide dismutase (MnSOD) in androgen-independent human prostate cancer (PC-3) cells' growth rate in vitro and in vivo. MnSOD levels were found to be lower in parental PC-3 cells compared to nonmalignant, immortalized human prostate epithelial cells (P69SV40T). To unravel the role of MnSOD in the prostate cancer phenotype, PC-3 cells were stably transfected with MnSOD cDNA plasmid. The MnSOD protein and activity levels in clones overexpressing MnSOD were increased seven- to eightfold. These cell lines showed elongated cell doubling time, reduced anchorage-independent growth in soft agar compared to parental PC-3 (Wt) cells, and reduced growth rate of PC-3 tumor xenografts in athymic nude mice. Flow cytometric studies showed an increase in membrane potential in the MnSOD-overexpressing clone (Mn32) compared to Wt and Neo cells. Also, production of extracellular H(2)O(2) was increased in the MnSOD-overexpressing clones. As determined by DNA cell cycle analysis, the proportion of cells in G(1) phase was enhanced by MnSOD overexpression. Therefore, MnSOD not only regulates cell survival but also affects PC-3 cell proliferation by retarding G(1) to S transition. Our results are consistent with MnSOD being a tumor suppressor gene in human prostate cancer.
本研究调查了抗氧化酶锰超氧化物歧化酶（MnSOD）在雄激素非依赖性人前列腺癌（PC-3）细胞体外和体内生长速率中的作用。与非恶性、永生化人前列腺上皮细胞（P69SV40T）相比，亲代PC-3细胞中的MnSOD水平较低。为了阐明MnSOD在前列腺癌表型中的作用，用MnSOD cDNA质粒稳定转染PC-3细胞。过表达MnSOD的克隆中MnSOD蛋白和活性水平增加了7至8倍。与亲代PC-3（野生型）细胞相比，这些细胞系显示细胞倍增时间延长，在软琼脂中不依赖贴壁生长减少，并且在无胸腺裸鼠中PC-3肿瘤异种移植物的生长速率降低。流式细胞术研究表明，与野生型和Neo细胞相比，过表达MnSOD的克隆（Mn32）中的膜电位增加。此外，过表达MnSOD的克隆中细胞外H(2)O(2)的产生增加。通过DNA细胞周期分析确定，MnSOD过表达增强了G(1)期细胞的比例。因此，MnSOD不仅调节细胞存活，还通过延缓G(1)期到S期的转变影响PC-3细胞增殖。我们的结果与MnSOD是人类前列腺癌中的肿瘤抑制基因一致。
