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雷帕霉素靶蛋白激活剂诱导自噬相关细胞死亡通过阻断 Akt 通路在人类肿瘤细胞。

Rhabdastrellic acid-A induced autophagy-associated cell death through blocking Akt pathway in human cancer cells.

机构信息

State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.

出版信息

PLoS One. 2010 Aug 17;5(8):e12176. doi: 10.1371/journal.pone.0012176.

DOI:10.1371/journal.pone.0012176
PMID:20808909
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2923153/
Abstract

BACKGROUND

Autophagy is an evolutionarily conserved protein degradation pathway. A defect in autophagy may contribute to tumorigenesis. Autophagy inducers could have a potential function in tumor prevention and treatment.

METHODOLOGY/PRINCIPAL FINDINGS: Our results showed that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge Rhabdastrella globostellata, inhibited proliferation of human cancer cell lines Hep3B and A549 and induced caspase-independent cell death in both the cell lines. Further investigation showed that Rhabdastrellic acid-A induced autophagy of cancer cells determined by YFP-LC3 punctation and increased LC3-II. The pretreatment with autophagy inhibitor 3-MA inhibited Rhabdastrellic acid-A-induced cell death. Knockdown of autophagy-related gene Atg5 inhibited Rhabdastrellic acid-A-induced cell death in A549 cells. Also, phospho-Akt and its downstream targets significantly decreased after treatment with Rhabdastrellic acid-A in both cancer cell lines. Transfection of constitutive active Akt plasmid abrogated autophagy and cell death induced by Rhabdastrellic acid-A.

CONCLUSIONS/SIGNIFICANCE: These results suggest that Rhabdastrellic acid-A could induce autophagy-associated cell death through blocking Akt pathway in cancer cells. It also provides the evidence that Rhabdastrellic acid-A deserves further investigation as a potential anticancer or cancer preventive agent.

摘要

背景

自噬是一种进化上保守的蛋白质降解途径。自噬缺陷可能导致肿瘤发生。自噬诱导剂可能在肿瘤预防和治疗中有潜在作用。

方法/主要发现：我们的结果表明，从海绵 Rhabdastrella globostellata 中分离得到的异马巴烷三萜 Rhabdastrellic acid-A 抑制人癌细胞系 Hep3B 和 A549 的增殖，并在这两种细胞系中诱导 caspase 非依赖性细胞死亡。进一步的研究表明，Rhabdastrellic acid-A 通过 YFP-LC3 点状和增加 LC3-II 诱导癌细胞自噬。自噬抑制剂 3-MA 的预处理抑制了 Rhabdastrellic acid-A 诱导的细胞死亡。自噬相关基因 Atg5 的敲低抑制了 A549 细胞中 Rhabdastrellic acid-A 诱导的细胞死亡。此外，Rhabdastrellic acid-A 处理后，两种癌细胞系中的磷酸化 Akt 及其下游靶标显著减少。组成型活性 Akt 质粒的转染消除了 Rhabdastrellic acid-A 诱导的自噬和细胞死亡。

结论/意义：这些结果表明，Rhabdastrellic acid-A 可通过阻断 Akt 通路诱导癌细胞中自噬相关的细胞死亡。它还提供了证据表明，Rhabdastrellic acid-A 值得进一步研究，作为一种潜在的抗癌或癌症预防剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/7add674c7325/pone.0012176.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/2b89f8fd0f8a/pone.0012176.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/32c71d6d145d/pone.0012176.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/e0b8c8b97848/pone.0012176.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/8e51459aeeac/pone.0012176.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/f9d2462e4674/pone.0012176.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/7e65b75db9db/pone.0012176.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/7add674c7325/pone.0012176.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/2b89f8fd0f8a/pone.0012176.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/32c71d6d145d/pone.0012176.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/e0b8c8b97848/pone.0012176.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/8e51459aeeac/pone.0012176.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/f9d2462e4674/pone.0012176.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/7e65b75db9db/pone.0012176.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf3d/2923153/7add674c7325/pone.0012176.g007.jpg

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