Voltage-gated Na+ channels confer invasive properties on human prostate cancer cells
Voltage-gated Na+ channels confer invasive properties on human prostate cancer cells
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DOI：
10.1007/s00424-003-1205-x
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发表时间：
2004-03-01
影响因子：
4.5
通讯作者：
Harper, JM
中科院分区：
文献类型：
--
作者：
Bennett, ES;Smith, BA;Harper, JM
前列腺癌是美国男性癌症死亡的第二大原因，估计每年导致37，000人死亡，通常是转移性疾病的结果。最初用于治疗转移性疾病的雄激素消融疗法不成功的后果是出现雄激素不敏感的前列腺癌，目前没有处方疗法。在这里，研究了三种相关的人前列腺癌细胞系，其用作这种主要形式的前列腺癌转移的模型，以确定电压门控钠通道表达/功能与前列腺癌转移（侵袭）潜力之间的相关性：非转移性的雄激素依赖性LNCaP LC细胞系和两种致瘤性增加的雄激素非依赖性子细胞系C4和C4-2。荧光体外侵袭实验表明，C4和C4-2细胞比LC细胞更具侵袭性。免疫印迹分析表明，电压门控钠通道的表达增加与细胞系的侵袭电位，这种增加的侵袭电位可以通过治疗与特定的电压门控钠通道抑制剂，河豚毒素（TTX）。这些数据表明，增加的电压门控钠通道表达和功能是这些人前列腺癌细胞的侵袭潜力增加所必需的。当人成人骨骼肌钠通道Na-v1.4在每个细胞系中瞬时表达时，侵入LC、C4和C4-2细胞的数量显著增加。通过TTX治疗，这种增加的侵袭性潜力降低至对照水平。这些数据首次表明单独的电压门控钠通道的表达足以增加非转移性（LC细胞）以及更具侵袭性的细胞（即，C4和C4-2细胞）。总之，这些数据表明，单独增加电压门控钠通道表达是必要的，足以增加一组人前列腺癌细胞系的侵袭潜力，作为前列腺癌转移的模型。
Prostate cancer is the second leading cause of cancer deaths in American males, resulting in an estimated 37,000 deaths annually, typically the result of metastatic disease. A consequence of the unsuccessful androgen ablation therapy used initially to treat metastatic disease is the emergence of androgen-insensitive prostate cancer, for which there is currently no prescribed therapy. Here, three related human prostate cancer cell lines that serve as a model for this dominant form of prostate cancer metastasis were studied to determine the correlation between voltage-gated sodium channel expression/function and prostate cancer metastatic (invasive) potential: the non-metastatic, androgen-dependent LNCaP LC cell line and two increasingly tumorogenic, androgen-independent daughter cell lines, C4 and C4-2. Fluorometric in vitro invasion assays indicated that C4 and C4-2 cells are more invasive than LC cells. Immunoblot analysis showed that voltage-gated sodium channel expression increases with the invasive potential of the cell line, and this increased invasive potential can be blocked by treatment with the specific voltage-gated sodium channel inhibitor, tetrodotoxin (TTX). These data indicate that increased voltage-gated sodium channel expression and function are necessary for the increased invasive potential of these human prostate cancer cells. When the human adult skeletal muscle sodium channel Na-v1.4 was expressed transiently in each cell line, there was a highly significant increase in the numbers of invading LC, C4, and C4-2 cells. This increased invasive potential was reduced to control levels by treatment with TTX. These data are the first to indicate that the expression of voltage-gated sodium channels alone is sufficient to increase the invasive potential of non-metastatic (LC cells) as well as more aggressive cells (i.e., C4 and C4-2 cells). Together, the data suggest that increased voltage-gated sodium channel expression alone is necessary and sufficient to increase the invasive potential of a set of human prostate cancer cell lines that serve as a model for prostate cancer metastasis.