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新型化合物 ChlA-F 通过上调人膀胱癌中的 Sestrin-2 诱导自噬依赖性抗癌作用。

New compound ChlA-F induces autophagy-dependent anti-cancer effect via upregulating Sestrin-2 in human bladder cancer.

机构信息

Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA.

Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

出版信息

Cancer Lett. 2018 Nov 1;436:38-51. doi: 10.1016/j.canlet.2018.08.013. Epub 2018 Aug 16.

DOI:10.1016/j.canlet.2018.08.013
PMID:30118841
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6245652/
Abstract

ChlA-F is a novel conformation-derivative of Cheliensisin A, styryl-lactone isolates that show potent anti-tumor potential in vivo and vitro. However, the anti-cancer activity and its potential mechanisms underlying ChlA-F action have never been explored. In the present study, we evaluated the potency of ChlA-F on autophagy-mediated anchorage-independent growth inhibition in human high-grade invasive bladder cancer (BC) cells. We found that ChlA-F treatment significantly inhibited anchorage-independent growth of human BC cells by inducing autophagy in a Sestrin-2 (SESN2)-dependent fashion. Our results revealed that ChlA-F treatment specifically induced SESN2 expression via increasing its transcription and mRNA stability. On one hand, ChlA-F treatment markedly attenuated Dicer protein abundance, in turn abolishing miR-27a maturation and further relieving miR-27a binding directly to SESN2 mRNA 3'UTR, thereby promoting SESN2 mRNA stabilization. On the other hand, ChlA-F treatment promoted Sp1 abundance and consequently mediated SESN2 transcription. These results demonstrate that its activation of the autophagic pathway through specifically promoting SESN2 expression mediates the anti-cancer effect of ChlA-F, which offers insights into the novel anti-cancer effect of ChlA-F on BC, as well as providing therapeutic alternatives against human BC.

摘要

ChlA-F 是一种新型的 Cheliensisin A 构象衍生物，是一种具有潜在抗肿瘤活性的苯乙烯内酯类化合物，在体内和体外均表现出很强的抗肿瘤活性。然而，ChlA-F 的抗癌活性及其潜在作用机制尚未得到探索。在本研究中，我们评估了 ChlA-F 对人高级浸润性膀胱癌（BC）细胞中自噬介导的无锚定生长抑制的作用。我们发现，ChlA-F 通过依赖 Sestrin-2（SESN2）的方式诱导自噬，显著抑制人 BC 细胞的无锚定生长。我们的结果表明，ChlA-F 治疗通过增加 SESN2 的转录和 mRNA 稳定性，特异性地诱导 SESN2 的表达。一方面，ChlA-F 治疗显著降低了 Dicer 蛋白的丰度，从而消除了 miR-27a 的成熟，并进一步解除了 miR-27a 对 SESN2 mRNA 3'UTR 的直接结合，从而促进了 SESN2 mRNA 的稳定。另一方面，ChlA-F 治疗促进了 Sp1 的丰度，从而介导了 SESN2 的转录。这些结果表明，它通过特异性促进 SESN2 的表达激活自噬途径，介导了 ChlA-F 的抗癌作用，为 ChlA-F 对 BC 的新的抗癌作用提供了深入的了解，并为治疗人类 BC 提供了新的选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/d44eb4e420a0/nihms-1511652-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/b4dcc779d37e/nihms-1511652-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/7fe713c29808/nihms-1511652-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/33d32fa73f22/nihms-1511652-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/235ee0c000b7/nihms-1511652-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/8d8fd1cacc0a/nihms-1511652-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/d44eb4e420a0/nihms-1511652-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/b4dcc779d37e/nihms-1511652-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/7fe713c29808/nihms-1511652-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/33d32fa73f22/nihms-1511652-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/235ee0c000b7/nihms-1511652-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/8d8fd1cacc0a/nihms-1511652-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538c/6245652/d44eb4e420a0/nihms-1511652-f0006.jpg

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