TY - JOUR
T1 - Autophagic flux modulation by Wnt/β-catenin pathway inhibition in hepatocellular carcinoma
AU - Turcios, Lilia
AU - Chacon, Eduardo
AU - Garcia, Catherine
AU - Eman, Pedro
AU - Cornea, Virgilius
AU - Jiang, Jieyun
AU - Spear, Brett
AU - Liu, Chunming
AU - Watt, David S.
AU - Marti, Francesc
AU - Gedaly, Roberto
N1 - 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.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062014537&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062014537&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0212538
DO - 10.1371/journal.pone.0212538
M3 - Article
C2 - 30794613
AN - SCOPUS:85062014537
SN - 1932-6203
VL - 14
JO - PLoS ONE
JF - PLoS ONE
IS - 2
M1 - e0212538
ER -
