Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
Endocr Relat Cancer. 2012 May 3;19(3):243-54. doi: 10.1530/ERC-11-0278. Print 2012 Jun.
Prostate cancer remains a leading cause of cancer-related death in men, largely attributable to distant metastases, most frequently to bones. Despite intensive investigations, molecular mechanisms underlying metastasis are not completely understood. Among prostate cancer-derived factors, parathyroid hormone-related peptide (PTHrP), first discovered as an etiologic factor for malignancy-induced hypercalcemia, regulates many cellular functions critical to tumor growth, angiogenesis, and metastasis. In this study, the role of PTHrP in tumor cell survival from detachment-induced apoptosis (i.e. anoikis) was investigated. Reduction of PTHLH (encoding PTHrP) gene expression in human prostate cancer cells (PC-3) increased the percentage of apoptotic cells when cultured in suspension. Conversely, overexpression of PTHrP protected prostate cancer cells (Ace-1 and LNCaP, both typically expressing low or undetectable basal PTHrP) from anoikis. Overexpression of nuclear localization signal (NLS)-defective PTHrP failed to protect cells from anoikis, suggesting that PTHrP-dependent protection from anoikis is an intracrine event. A PCR-based apoptosis-related gene array showed that detachment increased expression of the TNF gene (encoding the proapoptotic protein tumor necrosis factor-α) fourfold greater in PTHrP-knockdown PC-3 cells than in control PC-3 cells. In parallel, TNF gene expression was significantly reduced in PTHrP-overexpressing LNCaP cells, but not in NLS-defective PTHrP overexpressing LNCaP cells, when compared with control LNCaP cells. Subsequently, in a prostate cancer skeletal metastasis mouse model, PTHrP-knockdown PC-3 cells resulted in significantly fewer metastatic lesions compared to control PC-3 cells, suggesting that PTHrP mediated antianoikis events in the bloodstream. In conclusion, nuclear localization of PTHrP confers prostate cancer cell resistance to anoikis, potentially contributing to prostate cancer metastasis.
前列腺癌仍然是男性癌症相关死亡的主要原因，主要归因于远处转移，最常转移至骨骼。尽管进行了深入研究，但转移的分子机制仍未完全了解。在前列腺癌衍生的因子中，甲状旁腺激素相关肽（PTHrP）最初被发现是恶性肿瘤引起高钙血症的病因因子，调节许多对肿瘤生长、血管生成和转移至关重要的细胞功能。在这项研究中，研究了 PTHrP 在肿瘤细胞逃避脱落诱导的细胞凋亡（即 anoikis）中的作用。在悬浮培养时，降低人前列腺癌细胞（PC-3）中 PTHLH（编码 PTHrP）基因的表达会增加凋亡细胞的百分比。相反，PTHrP 的过表达可保护前列腺癌细胞（Ace-1 和 LNCaP，两者通常表达低或无法检测到基础 PTHrP）免受 anoikis。核定位信号（NLS）缺陷的 PTHrP 的过表达不能保护细胞免受 anoikis，这表明 PTHrP 依赖的对 anoikis 的保护是一种胞内事件。基于 PCR 的凋亡相关基因阵列显示，在 PTHrP 敲低的 PC-3 细胞中，与对照 PC-3 细胞相比，脱落会使 TNF 基因（编码促凋亡蛋白肿瘤坏死因子-α）的表达增加四倍。同时，在 PTHrP 过表达的 LNCaP 细胞中，TNF 基因的表达显著降低，但在 NLS 缺陷的 PTHrP 过表达的 LNCaP 细胞中，与对照 LNCaP 细胞相比，TNF 基因的表达显著降低。随后，在前列腺癌骨转移小鼠模型中，与对照 PC-3 细胞相比，PTHrP 敲低的 PC-3 细胞导致转移灶明显减少，这表明 PTHrP 在血液中介导抗 anoikis 事件。总之，PTHrP 的核定位赋予前列腺癌细胞对 anoikis 的抗性，可能有助于前列腺癌转移。
