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Wnt/β-catenin 通路抑制调控肝癌自噬流。

Autophagic flux modulation by Wnt/β-catenin pathway inhibition in hepatocellular carcinoma.

机构信息

Department of Surgery, Transplant Center, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.

Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America.

出版信息

PLoS One. 2019 Feb 22;14(2):e0212538. doi: 10.1371/journal.pone.0212538. eCollection 2019.

DOI:10.1371/journal.pone.0212538
PMID:30794613
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6386480/
Abstract

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/β-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells.

摘要

自噬将细胞成分靶向到溶酶体依赖性降解中，降解产物可能被回收用于蛋白质合成，并用于能量产生。自噬在细胞内稳态和许多生理和病理过程的调节中也起着关键作用，并促使人们研究新的药物来影响肝细胞癌 (HCC) 中的异常自噬。2,5-二氯-N-(2-甲基-4-硝基苯基)苯磺酰胺 (FH535) 是 Wnt/β-连环蛋白通路的合成抑制剂，对不同类型的癌细胞具有抗增殖和抗血管生成作用。FH535 与索拉非尼联合使用可促进 HCC 和肝癌干细胞增殖的协同抑制，部分原因是同时破坏线粒体呼吸和糖酵解。我们证明 FH535 可在小鼠异种移植模型中降低 HCC 肿瘤的进展。我们首次显示了 FH535 衍生物 FH535-N 单独和与索拉非尼联合使用对 HCC 细胞增殖的抑制作用。我们的研究揭示了 FH535 和其衍生物 (FH535-N) 通过破坏 HCC 细胞中的自噬流来抑制 Wnt/β-连环蛋白通路的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/eb8c966c471b/pone.0212538.g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/2749b76f62a8/pone.0212538.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/32dff6c785b8/pone.0212538.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/aa80e201ddd3/pone.0212538.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/1aa4031b5624/pone.0212538.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/44a75085153f/pone.0212538.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/184d59931fdd/pone.0212538.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/cc684a0956a2/pone.0212538.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/47ab92208a71/pone.0212538.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/61b16e46b1c1/pone.0212538.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/a75b8586d0ed/pone.0212538.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/eb8c966c471b/pone.0212538.g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/2749b76f62a8/pone.0212538.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/32dff6c785b8/pone.0212538.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/aa80e201ddd3/pone.0212538.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/1aa4031b5624/pone.0212538.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/44a75085153f/pone.0212538.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/184d59931fdd/pone.0212538.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/cc684a0956a2/pone.0212538.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/47ab92208a71/pone.0212538.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/61b16e46b1c1/pone.0212538.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/a75b8586d0ed/pone.0212538.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d614/6386480/eb8c966c471b/pone.0212538.g011.jpg

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