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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This research was supported by the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558). The research was also supported by the Redox Metabolism Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).
S1 Table. Antibodies used for western blot. https://doi.org/10.1371/journal.pone.0212538.s001 (TIF)
S1 Fig. β-catenin knockdown induced changes in LC3II and p62 protein levels in Huh7 cells. https://doi.org/10.1371/journal.pone.0212538.s002 (TIF)
S2 Fig. Effect of FH535 and FH535-N in combination with sorafenib on the protein levels of autophagy markers LC3B II and p62. https://doi.org/10.1371/journal.pone.0212538.s003 (TIF)
Turcios, Lilia; Chacon, Heather E.; Garcia, Catherine; Eman, Pedro; Cornea, Virgilius; Jiang, Jieyun; Spear, Brett T.; Liu, Chunming; Watt, David S.; Marti, Francesc; and Gedaly, Roberto, "Autophagic Flux Modulation by Wnt/β-Catenin Pathway Inhibition in Hepatocellular Carcinoma" (2019). Surgery Faculty Publications. 39.
S1 Table. Antibodies used for western blot.
journal.pone.0212538.s002.tif (135 kB)
S1 Fig. β-catenin knockdown induced changes in LC3II and p62 protein levels in Huh7 cells.
journal.pone.0212538.s003.tif (243 kB)
S2 Fig. Effect of FH535 and FH535-N in combination with sorafenib on the protein levels of autophagy markers LC3B II and p62.