Neuregulin promotes autophagic cell death of prostate cancer cells
Neuregulin promotes autophagic cell death of prostate cancer cells
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DOI：
10.1002/pros.10200
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发表时间：
2003-05-01
期刊：
影响因子：
2.8
通讯作者：
Pinkas-Kramarski, R
中科院分区：
文献类型：
--
作者：
Tal-Or, P;Di-Segni, A;Pinkas-Kramarski, R
背景前列腺癌是男性最常见的癌症之一。已在前列腺肿瘤中鉴定出表皮生长因子受体（EGFR）的自分泌/旁分泌生长因子，表明EGFR在前列腺癌进展中的作用。雄激素依赖性前列腺癌细胞系LNCaP表达EGFR以及该家族的两个额外成员; ErbB-2和ErbB-3，其可以被神经调节蛋白（NRG）亚型激活。研究ErbB配体对LNCaP细胞活力的影响。在本研究中，我们研究了NRG对LNCaP细胞的生长和生存的影响，在没有雄激素模拟物的情况下，通过MTT法，流式细胞仪分析，细胞核染色，和蛋白质印迹。我们的研究结果表明，NRG激活ErbB-2/ErbB-3异二聚体，并诱导LNCaP细胞的细胞死亡。相反，EGF激活ErbB-1/ErbB-1或ErbB-1/ErbB-2二聚体并诱导细胞生长和存活。有趣的是，用PI 3 K抑制剂处理的LNCaP细胞经历细胞死亡，但用NRG和PI 3 K抑制剂处理的细胞作为对照细胞存活，表明PI 3 K途径可能介导NRG诱导的细胞死亡。广谱半胱天冬酶抑制剂苄氧羰基-Val-Ala-Asp-fluoromethylketone（Z-VAD-FMK）不能抑制NRG诱导的细胞死亡。然而，NRG诱导的细胞死亡可被11型细胞死亡抑制剂3-甲基腺嘌呤抑制。这些结果表明，NRG通过PI 3 K依赖性途径诱导LNCaP细胞的11型细胞死亡。(C)2003 Wiley-Liss，Inc.
BACKGROUND. Prostate cancer is one of the most frequently diagnosed cancers in males. Autocrine/paracrine growth factors for the epidermal growth factor receptor (EGFR) have been identified in prostate tumors suggesting a role for EGFR in the progression of prostate cancer. The androgen-dependent prostate cancer cell line, LNCaP, expresses the EGFR as well as two additional members of the family; ErbB-2 and ErbB-3, which can be activated by neuregulin (NRG) isoforms. The effect of ErbB ligands on the viability of LNCaP cells was studied.METHODS. In the present study, we examined the effect of NRG on LNCaP cell growth and survival in the absence of androgen mimetic by the MTT assay, FACS analysis, nuclei staining, and Western blotting.RESULTS. Our results demonstrate that NRG activates ErbB-2/ErbB-3 heterodimers and induces cell death of LNCaP cells. By contrast, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers and induces cell growth and survival. Interestingly, LNCaP cells treated with PI3K inhibitor underwent cell death but cells treated with both NRG and PI3K inhibitor survived as the control cells, indicating that the PI3K pathway may mediate NRG-induced cell death. NRG-induced cell death was not inhibited by the broad-spectrum caspases inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK). However, NRG-induced cell death was inhibited by type 11 cell death inhibitor, 3-methyladenine.CONCLUSIONS. These results suggest that NRG induces type 11 cell death of LNCaP cells through PI3K-dependent pathway. (C) 2003 Wiley-Liss, Inc.