Role of cyclophilin B in tumorigenesis and cisplatin resistance in hepatocellular carcinoma in humans

Kim, Yeonghwan; Jang, Miran; Lim, Sung‐Jig; Won, Hyeran; Yoon, Kyung‐Sik; Park, Jaehoon; Kim, Hyo Jong; Kim, Byung-Ho; Park, Won-Sang; Ha, Joohun; Kim, Sung‐Soo

doi:10.1002/hep.24539

Cited by 59 publications

(65 citation statements)

References 38 publications

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“…This is inconsistent with the results of a previous report showing that HIF-1a transcriptionally upregulates CypB under hypoxia. 16 Thus, it is possible that hypoxia-mediated CypB gene induction is due, at least in part, to HIF-1a activation. However, under the conditions employed in this study, a site-directed mutagenesis in the ATF6 binding site prevented hypoxia-induced upregulation of CypB.…”

Section: Discussionmentioning

confidence: 99%

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Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia

Jeong

Kim

et al. 2013

Cell Death Differ

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The regulation of CCAAT/enhancer-binding protein-homologous protein (CHOP), an endoplasmic reticulum (ER) stress-response factor, is key to cellular survival. Hypoxia is a physiologically important stress that induces cell death in the context of the ER, especially in solid tumors. Although our previous studies have suggested that Cyclophilin B (CypB), a molecular chaperone, has a role in ER stress, currently, there is no direct information supporting its mechanism under hypoxia. Here, we demonstrate for the first time that CypB is associated with p300 E4 ligase, induces ubiquitination and regulates the proteasomal turnover of CHOP, one of the well-known pro-apoptotic molecules under hypoxia. Our findings show that CypB physically interacts with the N-terminal a-helix domain of CHOP under hypoxia and cooperates with p300 to modulate the ubiquitination of CHOP. We also show that CypB is transcriptionally induced through ATF6 under hypoxia. Collectively, these findings demonstrate that CypB prevents hypoxia-induced cell death through modulation of ubiquitin-mediated CHOP protein degradation, suggesting that CypB may have an important role in the tight regulation of CHOP under hypoxia.

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Section: Discussionmentioning

confidence: 99%

“…Immunofluorescence microscopy was performed as described previously. 16 Images were taken using the laser-scanning confocal microscope. For quantification, cells for each condition were analyzed in three sets.…”

Section: Methodsmentioning

confidence: 99%

Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia

Jeong

Kim

et al. 2013

Cell Death Differ

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“…Although the proteasome pathway rapidly degrades HIF-1a under normoxia, this protein is stable under hypoxia, where it translocates to the nucleus and binds to hypoxia response elements (HREs) within the promoter of its target genes. Significant evidence indicates that HIF-1a plays an important role in the resistance to chemotherapy of hepatocellular carcinoma (12,13). Hence, inhibition of the HIF-1a pathway is a promising approach for the treatment of hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

Cai

Liu

Zhu

et al. 2014

Molecular Cancer Therapeutics

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Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1a (HIF-1a) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1a expression by decreasing HIF-1a protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1a protein, decreased the HIF-1a transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1a is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1a is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers. Mol Cancer Ther; 13(3); 630-42. Ó2013 AACR.

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“…In the present study, 7 of the downregulated proteins in the A549 cells were identified by MS, and with the exception of MST, their downregulation favored the anti-tumor activity of Umb. Cyclophilin B is a ubiquitously expressed protein in normal cells and tissues, but protects cancer cells against apoptosis induced by cisplatin, hypoxia and oxidative stresses (26). The protein increases tumor growth, angiogenesis and resistance to therapy (26).…”

Section: Discussionmentioning

confidence: 99%

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

et al. 2016

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Abstract. Umbelliprenin (Umb), a natural coumarin, has demonstrated anti-tumor activities, both in vitro and particularly in vivo, in several types of cancer, including lung cancer. The present study aimed to identify molecular targets of Umb using a high-throughput approach. Lung cancer cell lines, QU-DB (large-cell lung carcinoma) and A549 (adenocarcinoma), were treated with Umb. Differentially-expressed proteins were identified using two-dimensional electrophoresis coupled to mass spectrometry. In the QU-DB cells, differential expression of proteins, including downregulation of the tumorigenic protein heat shock protein 90 kDa and upregulation of the potential anti-tumor proteins Nipsnap1 and glycine-tRNA ligase (GRS), suggested that Umb is a strong anti-tumor compound. In the A549 cells, differential expression of proteins indicated possible contradictory effects of Umbregarding tumorigenesis, which included downregulation of the tumorigenic protein cyclophilin and the tumor suppressor MST, and upregulation of stathmin (tumorigenic) and calreticulin. Calreticulun, in addition to GRS in QU-DB cells, stimulates anti-tumor immune responses in vivo. To the best of our knowledge, the present study is the first to use a high-throughput approach to identify targets of Umb in cancer. These molecular targets suggested that Umb may exhibit stronger in vitro anti-tumor activity against the large-cell carcinoma model than the adenocarcinoma model. Furthermore, it has been reported that Umb exhibits higher cytotoxicity against QU-DB cells than A549 cells in vitro, and significant Umb anti-tumor activity against lung cancer in vivo, which is consistent with previously published literature. In each cell type, immune-associated molecules were upregulated, indicating that this naturally occurring compound exhibits marked anti-tumor activity in vivo. However, further studies that investigate the effect of Umb in different in vitro models of cancer are required.

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Role of cyclophilin B in tumorigenesis and cisplatin resistance in hepatocellular carcinoma in humans

Cited by 59 publications

References 38 publications

Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia

Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

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