Neuregulin promotes incomplete autophagy of prostate cancer cells that is independent of mTOR pathway inhibition.
Neuregulin promotes incomplete autophagy of prostate cancer cells that is independent of mTOR pathway inhibition.
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DOI：
10.1371/journal.pone.0036828
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pinkas-Kramarski R
中科院分区：
文献类型：
--
作者：
Schmukler E;Shai B;Ehrlich M;Pinkas-Kramarski R
已经在前列腺肿瘤中描述了激活ErbB受体的生长因子。雄激素依赖性前列腺癌细胞系LNCaP表达ErbB-1、ErbB-2和ErbB-3受体酪氨酸激酶。以前，已经证明NRG激活ErbB-2/ErbB-3异二聚体以诱导LNCaP细胞死亡，而EGF激活ErbB-1/ErbB-1或ErbB-1/ErbB-2二聚体以诱导细胞生长和存活。还证明了PI 3 K抑制剂抑制这种细胞死亡，表明在雄激素剥夺的LNCaP细胞中，NRG激活与细胞死亡相关的PI 3 K依赖性途径。在本研究中，我们证明，NRG诱导自噬LNCaP细胞，使用LC 3作为标记。然而，NRG诱导的自噬可能是不完全的，因为p62水平升高。我们还证明了NRG诱导的自噬不依赖于哺乳动物雷帕霉素靶蛋白（mTOR）抑制，因为NRG诱导Akt和S6 K活化。有趣的是，N-乙酰半胱氨酸（NAC）抑制活性氧（ROS），抑制NRG诱导的自噬和细胞死亡。我们的研究还确定JNK和Beclin 1是NRG诱导的自噬和细胞死亡的重要成分。NRG诱导JNK磷酸化升高，而NAC抑制JNK磷酸化。此外，JNK抑制剂抑制NRG诱导的自噬和细胞死亡。此外，在过表达Bcl-2的细胞或表达针对Beclin 1的sh-RNA的细胞中，NRG的作用，即诱导自噬和细胞死亡，被抑制。因此，在LNCaP细胞中，NRG诱导依赖于ROS水平的不完全自噬和细胞死亡。NRG的这些作用由激活JNK和Beclin 1的信号通路介导，但不依赖于mTOR抑制。
Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death. In the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited. Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition.
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影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung
影响因子：
4.8
作者：
Noda, T;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
8
作者：
Grasso, AW;Wen, DZ;Kung, HJ
通讯作者：
Kung, HJ
影响因子：
7.4
作者：
ARUOMA, OI;HALLIWELL, B;BUTLER, J
通讯作者：
BUTLER, J
影响因子：
64.8
作者：
Kuma, A;Hatano, M;Mizushima, N
通讯作者：
Mizushima, N