Tumor suppression and apoptosis of human prostate carcinoma mediated by a genetic locus within human chromosome 10pter-q11.

Prostate cancer is the second leading cause of male cancer deaths in the United States. Yet, despite a large international effort, little is known about the molecular mechanisms that underlie this devastating disease. Prostate secretory epithelial cells and androgen-dependent prostate carcinomas undergo apoptosis in response to androgen deprivation and, furthermore, most prostate carcinomas become androgen independent and refractory to further therapeutic manipulations during disease progression. Definition of the genetic events that trigger apoptosis in the prostate could provide important insights into critical pathways in normal development as well as elucidate the perturbations of those key pathways in neoplastic transformation. We report the functional definition of a novel genetic locus within human chromosome 10pter-q11 that mediates both in vivo tumor suppression and in vitro apoptosis of prostatic adenocarcinoma cells. A defined fragment of human chromosome 10 was transferred via microcell fusion into a prostate adenocarcinoma cell line. Microcell hybrids containing only the region 10pter-q11 were suppressed for tumorigenicity following injection of microcell hybrids into nude mice. Furthermore, the complemented hybrids undergo programmed cell death in vitro via a mechanism that does not require nuclear localization of p53. These data functionally define a novel genetic locus, designated PAC1, for prostate adenocarcinoma 1, involved in tumor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in prostatic adenocarcinoma. IMAGES:

前列腺癌是美国男性癌症相关死亡的第二大常见病因。尽管全球已开展大量研究工作，但学界对这种恶性疾病背后的分子机制仍知之甚少。
前列腺分泌上皮细胞与雄激素依赖性前列腺癌在雄激素剥夺刺激下会发生细胞凋亡（apoptosis）；此外，多数前列腺癌在疾病进展过程中会转变为雄激素非依赖型，并对后续治疗手段产生耐药性。
阐明前列腺内触发细胞凋亡的遗传事件，既能为正常发育中的关键通路研究提供重要见解，也能揭示这些核心通路在肿瘤转化过程中的异常改变。
本研究对人类10号染色体pter-q11区域内的全新遗传位点进行了功能定义，该位点可同时介导前列腺腺癌细胞的体内肿瘤抑制活性与体外细胞凋亡过程。
研究人员通过微细胞融合技术，将一段明确的人类10号染色体片段导入前列腺腺癌细胞系中。仅携带10pter-q11区域的微细胞杂交细胞，在被注射至裸鼠体内后，其致瘤性受到抑制。
此外，经基因互补的杂交细胞在体外会发生程序性细胞死亡（programmed cell death），且该过程无需p53的核定位。
本研究通过上述实验数据，功能性定义了一个全新的遗传位点并将其命名为PAC1（前列腺癌1型，Prostate Adenocarcinoma 1），该位点参与人类前列腺癌的肿瘤抑制过程；同时研究结果强烈提示，前列腺腺癌的细胞死亡通路可被功能性恢复。
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