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

Lilia Turcios; Eduardo Chacon; Catherine Garcia; Pedro Eman; Virgilius Cornea; Jieyun Jiang; Brett Spear; Chunming Liu; David S. Watt; Francesc Marti; Roberto Gedaly

doi:10.1371/journal.pone.0212538

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

Lilia Turcios, Eduardo Chacon, Catherine Garcia, Pedro Eman, Virgilius Cornea, Jieyun Jiang, Brett Spear, Chunming Liu, David S. Watt, Francesc Marti, Roberto Gedaly

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English
Article number	e0212538
Journal	PLoS ONE
Volume	14
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0212538
State	Published - Feb 2019

Bibliographical note

Publisher Copyright:
© 2019 Turcios et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	P30CA177558

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pone.0212538

Cite this

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title = "Autophagic flux modulation by Wnt/β-catenin pathway inhibition in hepatocellular carcinoma",

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.",

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AU - Eman, Pedro

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AU - Jiang, Jieyun

AU - Spear, Brett

AU - Liu, Chunming

AU - Watt, David S.

AU - Marti, Francesc

AU - Gedaly, Roberto

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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