Prostate cancer cells increase androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; A possible mechanism of hormone-resistance of prostate cancer cells
Prostate cancer cells increase androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; A possible mechanism of hormone-resistance of prostate cancer cells
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DOI：
10.1080/07357900601130698
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发表时间：
2007-01-01
影响因子：
2.4
通讯作者：
Matsumoto, Tetsuro
中科院分区：
文献类型：
--
作者：
Fujimoto, Naohiro;Miyamoto, Hiroshi;Matsumoto, Tetsuro
尽管雄激素超敏反应是前列腺癌中激素抵抗的可能途径之一，但雄激素超敏反应的机制仍然很大程度上未知。使用由雄激素敏感的LNCaP细胞通过肿瘤坏死因子α长期治疗而建立的雄激素过敏的前列腺癌细胞LN-TR2，我们探索了前列腺癌细胞中雄激素过敏的机制，从而可能在激素抵抗中发挥作用。我们检查了 LNCaP 和 LN-TR2 细胞中雄激素受体 (AR) DNA 序列以及 AR 和 8 个 AR 辅因子的表达水平。结果，LN-TR2 细胞中的 AR DNA 中没有出现新的突变。我们观察到，与 LNCaP 细胞相比，LN-TR2 中雄激素处理后核 AR 的表达更高，并且 2 个 AR 共激活剂 ARA55 和 TIF2 也更高。 ARA55 或 TIF2 的过表达增强了 LNCaP 细胞中雄激素诱导的 AR 转录活性。在存在这些 AR 共激活剂的情况下，即使在低浓度的雄激素下也观察到 AR 活性。在6名患者中的2名中，激素抵抗肿瘤的癌细胞中ARA55的表达水平高于激素敏感肿瘤的癌细胞。综上所述，我们的结果表明前列腺癌细胞通过核AR和AR共激活剂的过度表达改变雄激素敏感性，从而导致前列腺癌细胞从雄激素依赖性向雄激素非依赖性转变。核AR和AR共激活剂的增加可能会引起前列腺癌细胞的雄激素过敏，从而在激素抵抗中发挥作用，至少在一些前列腺癌患者中是这样。
Although androgen-hypersensitivity is one of the possible pathways of hormone-resistance in prostate cancer, the mechanisms of androgen- hypersensitivity are still largely unknown. Using androgen- hypersensitive prostate cancer cells LN-TR2, established from androgensensitive LNCaP cells by the long term treatment with tumor necrosis factor alpha, we explored the mechanisms of androgen- hypersensitivity in prostate cancer cells which may thus play a role in hormone-resistance. We examined the androgen receptor (AR) DNA sequence and the expression levels of AR and 8 AR cofactors in LNCaP and LN-TR2 cells. As a result, no novelmutation was developed in AR DNA in LN-TR2 cells. We observed higher expressions of nuclear AR upon androgen- treatment and 2 AR coactivators, ARA55 and TIF2, in LN-TR2 compared to LNCaP cells. An overexpression of ARA55 or TIF2 enhanced androgen- induced AR transcriptional activity in LNCaP cell. In the presence of those AR coactivators, AR activity was observed even at low concentrations of androgen. In 2 of 6 patients, the expression level of ARA55 was higher in cancer cells in hormone- resistant tumor than those in hormone- sensitive tumor. Taken together, our results suggest that prostate cancer cells change androgen- sensitivity by an overexpression of nuclear AR and AR coactivators, thus, resulting in transition from androgen-dependent to androgen- independent prostate cancer cells. An increase in nuclear AR and AR coactivators may cause androgen- hypersensitivity of prostate cancer cells and thus play a role in hormone- resistance, at least in some patients with prostate cancer.