Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition.

Journal of Bioenergetics and Biomembranes
Su Jong YuChung Yong Kim

Abstract

3-bromopyruvate (3-BP), a hexokinase (HK) II inhibitor, promotes tumor cell death by inducing endoplasmic reticulum (ER) stress in human hepatocellular carcinoma (HCC) cell lines. Protein disulfide isomerase (PDI) is an essential folding catalyst and attenuates ER stress by folding the misfolded proteins. We examined if PDI is expressed in hypoxic HCC cells, and evaluated its inhibition potentiated HK II inhibitor-induced ER stress in hypoxic HCC cells. HCC apoptotic cell death was assessed by DAPI staining and apoptotic signaling pathways were explored by immunoblot analysis. An in vivo model of HCC was established in C3H mice intradermally with implanted MH134 cells. 3-BP with/without a PDI inhibitor (bacitracin) was subsequently administered. The anti-tumor efficacies were evaluated by measuring tumor volumes and quantifying apoptotic cells and microvessel densities (MVDs). HCC cells were found to express PDI in a hypoxia-inducible manner. The simultaneous treatment of bacitracin and 3-BP enhanced 3-BP-induced apoptosis. This enhancement was attributed to increased ER stress and JNK activation compared to the cells treated with just 3-BP. In an in vivo model of HCC, tumor growth was significantly suppressed in mice co-treate...Continue Reading

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Citations

Feb 7, 2014·Endocrine-related Cancer·Ales VichaKarel Pacak
Mar 29, 2014·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Sara E Patterson, Caroline N Dealy
May 21, 2015·Journal of Cancer Research and Clinical Oncology·Min-Sun KwakChung Yong Kim
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Mar 17, 2019·International Journal of Molecular Sciences·Jeong-Ju YooJung-Hwan Yoon
May 12, 2017·Frontiers in Oncology·Marco CorazzariMauro Piacentini

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