Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

Podkalicka, Paulina; Mucha, Olga; Kruczek, Szczepan; Biela, Anna; Andrysiak, Kalina; Stępniewski, Jacek; Mikulski, Maciej; Gałęzowski, Michał; Sitarz, Kamil S.; Brzózka, Krzysztof; Józkowicz, Alicja; Dulak, Józef; Łoboda, Agnieszka

doi:10.3390/biom10010143

Cited by 13 publications

(14 citation statements)

References 37 publications

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“…The authors show that when heme synthesis was upregulated, it led to incorporation of radiolabeled fumarate into heme via succinate and succinyl-CoA [ 20 ]. More recently it has been shown that fumarate hydratase (FH) and HO-1 are synthetically lethal [ 26 , 27 ]. FH deficient cells accumulated fumarate and succinate and had increased expression of HO-1.…”

Section: Resultsmentioning

confidence: 99%

Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells

Carr

Garcia

Scaffa

et al. 2020

IJMS

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Heme oxygenase-1 is induced by many cellular stressors and catalyzes the breakdown of heme to generate carbon monoxide and bilirubin, which confer cytoprotection. The role of HO-1 likely extends beyond the simple production of antioxidants, for example HO-1 activity has also been implicated in metabolism, but this function remains unclear. Here we used an HO-1 knockout lung cell line to further define the contribution of HO-1 to cellular metabolism. We found that knockout cells exhibit reduced growth and mitochondrial respiration, measured by oxygen consumption rate. Specifically, we found that HO-1 contributed to electron transport chain activity and utilization of certain mitochondrial fuels. Loss of HO-1 had no effect on intracellular non-heme iron concentration or on proteins whose levels and activities depend on available iron. We show that HO-1 supports essential functions of mitochondria, which highlights the protective effects of HO-1 in diverse pathologies and tissue types. Our results suggest that regulation of heme may be an equally significant role of HO-1.

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Section: Resultsmentioning

confidence: 99%

Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells

Carr

Garcia

Scaffa

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Numerous studies have proved that the anti-inflammatory, antioxidant, pro-angiogenic, anti-thrombotic, and anti-apoptotic effects of HO-1 are derived from its catabolic byproducts, CO and biliverdin, which render HO-1 as a tissue protector and a good candidate for investigating new therapeutic interventions [1,8,13]. However, several studies have extensively demonstrated the positive role of HO-1 in cancer progress [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells

et al. 2020

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Heme oxygenase-1 (HO-1) has several important roles in hepatocytes in terms of anti-inflammation, anti-apoptosis, and antioxidant properties. Interleukin-6 (IL-6) is a pleiotropic cytokine associated with liver regeneration and protection against injury. The aim of this study was to determine the potential crosstalk between HO-1 and IL-6, and to elucidate the signaling pathways involved in the induction of HO-1 by IL-6 in human hepatoma cells. Ectopic overexpression of HO-1 not only attenuated cell proliferation in vitro and in vivo, but also blocked the reactive oxygen species (ROS) induced by H2O2 and the pyocyanin in HepG2 or Hep3B cells. IL-6 expression was negatively regulated by HO-1, while IL-6 induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and HO-1 gene expression in HepG2 cells. The co-transfected HO-1 reporter vector and a protein inhibitor of the activated STAT3 (PIAS3) expression vector blocked the IL-6-induced HO-1 reporter activity. Both interferon γ and interleukin-1β treatments induced STAT1 but not STAT3 phosphorylation, which had no effects on the HO-1 expression. Treatments of AG490 and luteolin blocked the JAK/STAT3 signaling pathways which attenuated IL-6 activation on the HO-1 expression. Our results indicated that HO-1 is the antitumor gene induced by IL-6 through the IL-6/JAK/STAT3 pathways; moreover, a feedback circuit may exist between IL-6 and HO-1 in hepatoma cells.

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“…On the other hand, we investigated whether brazilin-induced HO-1 expression, but it was not observed (data not shown). Moreover, novel HO-1 inhibition tools were reported such as arylethanolimidazole derivatives in cancer [ 49 ], caffeic acid phenethyl ester in diabetes [ 50 ] and fumarate hydratase as target genes in cancer [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Roles of JNK/Nrf2 Pathway on Hemin-Induced Heme Oxygenase-1 Activation in MCF-7 Human Breast Cancer Cells

et al. 2020

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Heme oxygenase-1 (HO-1) is highly induced in various human disease states, including cancer, indicating that HO-1 is an emerging target of cancer therapy. In this study, we investigated that the mechanisms of hemin-induced HO-1 expression and its signaling pathways in human breast cancer cell. We used MCF-7 cells, a human breast cancer cell line. Hemin increased HO-1 expression in MCF-7 cells in a dose- and time-dependent manner. Hemin enhanced HO-1 expression through the activation of c-Jun N-terminal kinases (JNK) signaling pathway. Hemin also induced activation of Nrf2, a major transcription factor of HO-1 expression. These responses in MCF-7 cells were completely blocked by pretreatment with brazilin, a HO-1 regulator. These results indicated that brazilin inhibits hemin-induced HO-1 expressions through inactivation of JNK/Nrf2 in MCF-7 cells. Thus, our findings suggest that HO-1 is an important anticancer-target of brazilin in human breast cancer.

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Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes

Cited by 13 publications

References 37 publications

Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells

Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells

Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells

Roles of JNK/Nrf2 Pathway on Hemin-Induced Heme Oxygenase-1 Activation in MCF-7 Human Breast Cancer Cells

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