PMID- 22350012 OWN - NLM STAT- MEDLINE DCOM- 20120716 LR - 20211021 IS - 1573-6881 (Electronic) IS - 0145-479X (Linking) VI - 44 IP - 1 DP - 2012 Feb TI - Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition. PG - 101-15 LID - 10.1007/s10863-012-9416-5 [doi] AB - 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-treated with bacitracin and 3-BP, and the percentages of apoptotic cells significantly increased and MVDs significantly decreased. These results demonstrated that PDI was induced in hypoxic HCC tissue and that PDI inhibition enhanced HK II inhibitor-induced anti-tumor efficacy synergistically via augmenting ER stress and anti-angiogenesis in vivo. Thus, blockage of PDI activity in combination with HK II inhibitor may be therapeutically useful in HCCs. FAU - Yu, Su Jong AU - Yu SJ AD - Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. FAU - Yoon, Jung-Hwan AU - Yoon JH FAU - Yang, Jong-In AU - Yang JI FAU - Cho, Eun Ju AU - Cho EJ FAU - Kwak, Min Sun AU - Kwak MS FAU - Jang, Eun Sun AU - Jang ES FAU - Lee, Jeong-Hoon AU - Lee JH FAU - Kim, Yoon Jun AU - Kim YJ FAU - Lee, Hyo-Suk AU - Lee HS FAU - Kim, Chung Yong AU - Kim CY LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120215 PL - United States TA - J Bioenerg Biomembr JT - Journal of bioenergetics and biomembranes JID - 7701859 RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (Indoles) RN - 0 (Pyruvates) RN - 1405-87-4 (Bacitracin) RN - 47165-04-8 (DAPI) RN - 63JMV04GRK (bromopyruvate) RN - EC 2.7.1.1 (Hexokinase) RN - EC 5.3.4.1 (Protein Disulfide-Isomerases) SB - IM MH - Animals MH - Antineoplastic Agents, Alkylating/*pharmacology MH - Apoptosis/*drug effects MH - Bacitracin MH - Carcinoma, Hepatocellular/*metabolism MH - Cell Line, Tumor MH - Endoplasmic Reticulum Stress/*drug effects MH - Hexokinase/*antagonists & inhibitors MH - Humans MH - Immunoblotting MH - Indoles MH - Male MH - Mice MH - Microvessels/pathology MH - Protein Disulfide-Isomerases/antagonists & inhibitors/*metabolism MH - Pyruvates/*pharmacology MH - Statistics, Nonparametric EDAT- 2012/02/22 06:00 MHDA- 2012/07/17 06:00 CRDT- 2012/02/22 06:00 PHST- 2011/12/27 00:00 [received] PHST- 2012/01/14 00:00 [accepted] PHST- 2012/02/22 06:00 [entrez] PHST- 2012/02/22 06:00 [pubmed] PHST- 2012/07/17 06:00 [medline] AID - 10.1007/s10863-012-9416-5 [doi] PST - ppublish SO - J Bioenerg Biomembr. 2012 Feb;44(1):101-15. doi: 10.1007/s10863-012-9416-5. Epub 2012 Feb 15.