Conversion of prostate cancer from hormone independency to dependency due to AMACR inhibition: involvement of increased AR expression and decreased IGF1 expression.
Conversion of prostate cancer from hormone independency to dependency due to AMACR inhibition: involvement of increased AR expression and decreased IGF1 expression.
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发表时间：
2009-07
影响因子：
2
通讯作者：
K. Takahara;H. Azuma;Takeshi Sakamoto;S. Kiyama;T. Inamoto;N. Ibuki;T. Nishida;H. Nomi;T. Ubai;N. Segawa;Y. Katsuoka
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作者：
K. Takahara;H. Azuma;Takeshi Sakamoto;S. Kiyama;T. Inamoto;N. Ibuki;T. Nishida;H. Nomi;T. Ubai;N. Segawa;Y. Katsuoka
雄激素非依赖性前列腺癌最终会发生转移，在这个阶段的患者可能无法进行根治性治疗。在这项研究中，我们研究了两个前列腺癌细胞系，LNCaP（雄激素依赖）和C4-2（雄激素非依赖）的基因表达谱，使用cDNA微阵列杂交。我们专注于α-甲基酰基-CoA消旋酶（AMACR）的表达，其在C4-2中的表达远高于LNCaP，并研究其在获得雄激素非依赖性癌症生长中的生物学作用。亚细胞组分的免疫组织化学和Western印迹分析显示，AMACR表达在C4-2比LNCaP强得多。与未处理的C4 -2相比，使用AMACR-siRNA抑制AMACR表达诱导C4-2中雄激素受体（AR）和B细胞易位基因1的表达增加，沿着与癌症进展相关的基因（包括胰岛素样生长因子I和血小板源性生长因子α）的表达降低。BrdU分析和MTT法显示，AMACR抑制剂可诱导C4-2细胞在去雄激素血清中的存活率显著下降，与LNCaP的结果一致，提示AMACR抑制剂可诱导AR表达增加，并诱导前列腺癌细胞由激素非依赖性向激素依赖性的特征性转变。我们认为AMACR抑制可能是治疗难治性前列腺癌患者的一种新策略。
Androgen-independent prostate cancer eventually develops metastasis, and radical treatment may not be possible for patients at this stage. In this study, we examined the gene-expression profiles of two prostate cancer cell lines, LNCaP (androgen-dependent) and C4-2 (androgen-independent), using cDNA-microarray hybridization. We focused on the expression of alpha-methylacyl-CoA racemase (AMACR), whose expression is much higher in C4-2 than in LNCaP, and investigated its biological role in acquisition of androgen-independent cancer growth. Immunohistochemistry and Western blot analysis of subcellular fractions revealed that AMACR expression was much stronger in C4-2 than in LNCaP. Inhibition of AMACR expression using AMACR-siRNA induced an increase in the expression of androgen receptor (AR) and B-cell translocation gene 1, along with a decrease in the expression of genes associated with cancer progression, including insulin-like growth factor I and platelet-derived growth factor alpha, in C4-2 with compared to non-treated C4-2. BrdU analysis and MTT assay demonstrated that AMACR inhibition induced a significant decrease of cell viability in C4-2 when cultured in androgen-depleted serum, becoming consistent with that of LNCaP, suggesting that AMACR inhibition may induce an increase in the expression of AR and characteristic conversion of prostate cancer cells from hormone independency to hormone dependency. We suggest that AMACR inhibition may be a new strategy for treatment of patients with hormone-refractory prostate cancer.