Nasu Y, Timme T L, Yang G, Bangma C H, Li L, Ren C, Park S H, DeLeon M, Wang J, Thompson T C
Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nat Med. 1998 Sep;4(9):1062-4. doi: 10.1038/2048.
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. 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.
虽然前列腺癌细胞最初通常对雄激素去除敏感，但它们最终会失去这种反应，并在没有雄激素类固醇的情况下继续存活、生长和扩散。雄激素去除疗法耐药的潜在机制大多仍不清楚。我们已经证明，在病理标本中，小窝蛋白水平升高与人类前列腺癌进展相关。在此我们表明，通过稳定转染的反义小窝蛋白-1 cDNA载体抑制小窝蛋白表达，可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表型。源自反义小窝蛋白克隆的原位生长肿瘤和低密度细胞培养物，在没有雄激素类固醇的情况下凋亡增加，而来自载体（对照）克隆和亲本细胞的同样生长的肿瘤和细胞对雄激素不敏感。使用代表性反义小窝蛋白克隆的研究表明，体内对雄激素耐药的选择与小窝蛋白水平增加相关，并且腺病毒介导的小窝蛋白表达会阻断雄激素敏感性。我们的结果确定了人类激素抵抗性前列腺癌的一个新候选基因，并表明雄激素不敏感性可能是转移性前列腺癌的一种固有特性。
