Srikanth S, Kraft A S
Division of Medical Oncology, University of Colorado Health Sciences Center, Denver 80262, USA.
Cancer Res. 1998 Feb 15;58(4):834-9.
Androgen withdrawal is a major therapeutic modality in the treatment of prostate cancer. Although tumors initially respond, they subsequently relapse, and these recurring tumors are androgen independent. To examine possible mechanisms to explain the androgen independence of prostate cancer, we have expressed cytokine response modifier A (CrmA), a competitive inhibitor of caspases, interleukin 1beta-converting enzyme-like proteases, which mediate apoptotic cell death, in the human androgen-dependent prostate cancer cell line LNCaP. LNCaP cells require androgens for continuous growth in culture and to form tumors in nude mice. The expression of CrmA in LNCaP cells prevented the decreased growth rate induced by androgen withdrawal in tissue culture. When CrmA-expressing LNCaP (LNCaP-CrmA) cells were implanted s.c. in nude mice, the tumors grew six times faster than parental cells. Androgen ablation by castration before tumor implantation suppressed the ability of control LNCaP cells expressing nonfunctional CrmA mutant (R291T) to form tumors, but LNCaP-CrmA cells formed tumors similar in size to those formed in normal mice. When orchiectomy was performed 10 days after tumor implantation, control LNCaP cells expressing a nonfunctional CrmA mutant (R291T) regressed, but LNCaP-CrmA tumors continued to grow. Thus, inhibition of caspases prevents androgen withdrawal-induced prostate cancer cell death, suggesting that caspase activation is normally an important part of this process.
雄激素去除是前列腺癌治疗中的一种主要治疗方式。尽管肿瘤最初会产生反应，但随后会复发，而且这些复发性肿瘤是雄激素非依赖性的。为了探究可能解释前列腺癌雄激素非依赖性的机制，我们在人雄激素依赖性前列腺癌细胞系LNCaP中表达了细胞因子反应调节因子A（CrmA），它是半胱天冬酶（caspases）的竞争性抑制剂，半胱天冬酶是介导细胞凋亡性死亡的白细胞介素1β转换酶样蛋白酶。LNCaP细胞在培养中持续生长以及在裸鼠体内形成肿瘤都需要雄激素。CrmA在LNCaP细胞中的表达阻止了组织培养中因雄激素去除而导致的生长速率下降。当将表达CrmA的LNCaP（LNCaP-CrmA）细胞皮下植入裸鼠时，肿瘤生长速度比亲代细胞快6倍。在肿瘤植入前通过去势进行雄激素去除抑制了表达无功能CrmA突变体（R291T）的对照LNCaP细胞形成肿瘤的能力，但LNCaP-CrmA细胞形成的肿瘤大小与正常小鼠中形成的肿瘤相似。当在肿瘤植入10天后进行睾丸切除术时，表达无功能CrmA突变体（R291T）的对照LNCaP细胞的肿瘤消退，但LNCaP-CrmA肿瘤继续生长。因此，抑制半胱天冬酶可防止雄激素去除诱导的前列腺癌细胞死亡，这表明半胱天冬酶激活通常是这一过程的重要组成部分。
