Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.
Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.
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DOI：
10.1371/journal.pone.0088556
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kung HJ
中科院分区：
文献类型：
--
作者：
Chang PC;Wang TY;Chang YT;Chu CY;Lee CL;Hsu HW;Zhou TA;Wu Z;Kim RH;Desai SJ;Liu S;Kung HJ
经历神经内分泌分化（NED）的前列腺癌（PCa）细胞在临床上与复发性去势抵抗性PCa的发展相关。越来越多的证据表明，自噬参与了神经内分泌肿瘤（neuroendocrine，NE）的发生、发展过程，PCa也是其中之一。为了阐明自噬对NED的影响，检查了雄激素敏感的PCa LNCaP细胞。用IL-6处理LNCaP细胞导致自噬的诱导。在没有雄激素的情况下，IL-6引起更强的自噬激活。在NED诱导中鉴定了类似的结果。用氯喹（CQ）抑制自噬显著降低NED。这一观察结果得到了beclin 1和Atg 5沉默实验的证实。进一步支持自噬在NED中的作用，我们发现，与原发性肿瘤对应物相比，LC 3在雄激素剥夺治疗后复发的PCa组织中上调。复发PCa组织中的LC 3染色显示类似于嗜铬粒蛋白A（CgA）（NED细胞的标志物）的染色的点状图案。自噬抑制可诱导IL-6诱导的NE分化的PCa细胞凋亡。因此，通过敲低beclin 1或Atg 5抑制自噬使NE分化的LNCaP细胞对化疗药物依托泊苷敏感。为了确定机制，分析了IL-6下游靶标的磷酸化。发现磷酸化AMPK增加和磷酸化mTOR减少，这意味着IL-6通过AMPK/mTOR途径调节自噬。这项研究最重要的是REST的发现，REST是一种参与自噬激活的神经元基因特异性转录抑制因子。IL-6处理后，REST表达下调。敲除实验表明，REST对NED和IL-6激活自噬至关重要。总之，我们的研究表明，自噬参与PCa的进展，并发挥细胞保护作用时，NED诱导PCa细胞的IL-6治疗。这些结果揭示了靶向自噬作为NE肿瘤联合治疗方案的一部分的潜力。
Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors.
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