Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells
Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells
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DOI：
10.1038/2048
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发表时间：
1998-09-01
期刊：
影响因子：
82.9
通讯作者：
Thompson, TC
中科院分区：
文献类型：
--
作者：
Nasu, Y;Timme, TL;Thompson, TC
尽管前列腺癌细胞最初通常对雄激素消融敏感，但它们最终会失去这种反应，在没有雄激素的情况下继续生存、生长和扩散。雄激素消融治疗抵抗的机制(S)大多仍不清楚。我们已经在病理标本中证明小窝蛋白水平升高与人类前列腺癌的进展有关(1)。在这里，我们展示了稳定表达小窝蛋白的反义小窝蛋白-1表达载体的抑制将雄激素不敏感的转移性小鼠前列腺癌细胞转化为雄激素敏感的表型。原位生长的肿瘤和来自反义小窝克隆的低密度细胞培养在没有雄激素的情况下增加了细胞的凋亡，而类似的生长的肿瘤和来自载体(对照)克隆和亲本细胞的细胞对雄激素不敏感。使用具有代表性的反义小窝蛋白克隆的研究表明，体内对雄激素抵抗的选择与小窝蛋白水平的增加相关，并且腺病毒介导的小窝蛋白表达阻断了雄激素的敏感性。我们的结果确定了一个新的男性激素抵抗前列腺癌的候选基因，并表明雄激素不敏感可能是转移性前列腺癌的固有属性。
Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens(1). Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.