Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib

Mayerhofer, Matthias; Gleixner, Karoline V.; Mayerhofer, Julia; Hoermann, Gregor; Jaeger, Eva; Aichberger, Karl J.; Ott, René G.; Greish, Khaled; Nakamura, Hideaki; Derdak, Sophia; Samorapoompichit, Puchit; Pickl, Winfried F.; Sexl, Veronika; Esterbauer, Harald; Schwarzinger, Ilse; Sillaber, Christian; Maeda, Hiroshi; Valent, Peter

doi:10.1182/blood-2006-11-055723

Cited by 87 publications

(101 citation statements)

References 57 publications

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“…In fact, micelles of styrene maleic acid containing 10 M ZnPP damaged oncogenic cells derived from patients with chronic myelogenous leukemia (6). Here, we confirm that ZnPP clearly suppresses cyclin D1 expression in BCL1 tumor cells and limits tumor progression.…”

Section: Discussionsupporting

confidence: 71%

“…Thus, ZnPP has potential therapeutic applications in controlling exaggerated bilirubin formation leading to neonatal jaundice (2). Moreover, because the by-products of the HO reaction, carbon monoxide and bilirubin, are antioxidants, the potential effects of ZnPP have been studied in numerous diseases, including cancer, such as chronic myelogenous leukemia (3)(4)(5)(6).…”

Section: Zinc Protoporphyrin IX (Znpp)mentioning

confidence: 99%

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Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Fernando

Wang

et al. 2009

Journal of Biological Chemistry

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Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and upregulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis. Zinc protoporphyrin IX (ZnPP)2 is a metabolite formed in trace amounts during heme biosynthesis. In this process, the final reaction is the chelation of zinc in the protoporphyrin ring, whereas heme is formed by chelation of iron in the ring. During periods of iron insufficiency or impaired iron utilization, ZnPP formation is enhanced. Clinically, ZnPP quantification is a sensitive and specific tool for measuring iron mineral status and metabolism (1). In addition, ZnPP regulates heme catabolism through competitively inhibiting the activity of heme oxygenase (HO), the rate-limiting enzyme in the heme degradation pathway that produces carbon monoxide and biliverdin. The latter is rapidly reduced to bilirubin by biliverdin reductase. Thus, ZnPP has potential therapeutic applications in controlling exaggerated bilirubin formation leading to neonatal jaundice (2). Moreover, because the by-products of the HO reaction, carbon monoxide and bilirubin, are antioxidants, the potential effects of ZnPP have been studied in numerous diseases, including cancer, such as chronic myelogenous leukemia (3-6).Whereas ZnPP has been largely studied in relation to its inhibition of HO activity, reports show that ZnPP could exert cellular effects independent of HO activity (7,8). In kinetic assays, ZnPP inhibited the soluble guanylyl cyclase activity independent of HO-1 (9). In vitro studies showed that ZnPP directly interacts with human immunodeficiency virus type 1 reverse transcriptase and modulates its activity (10). We showed that ZnPP induces the expression of HMOX1 and TP53 genes and localizes to the nucleus (11). Although the underling mechanism is unknown, zinc mesoporphyrin, another analogue of heme, has been shown to induce HMOX1 expression by accelerating Bach1 protein degradation (12). Heme itself can affect gene expression by associating with transcription factors (13,14). Th...

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Section: Discussionsupporting

confidence: 71%

Section: Zinc Protoporphyrin IX (Znpp)mentioning

confidence: 99%

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Fernando

Wang

et al. 2009

Journal of Biological Chemistry

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“…Recombinant VSV-G pseudotyped lentiviruses were produced as described previously. 41 HMC-1 and Ton.Kit.D816V cells were transduced in the presence of polybrene (7 g/mL) and were selected with puromycin (2 g/mL) for 48 hours. Knockdown of STAT5 was confirmed by immunoblotting and knockdown of KIT by fluorescence-activated cell sorting analysis.…”

Section: Knockdown Of Kit and Stat5mentioning

confidence: 97%

“…At 12 hours, cells were harvested and bound radioactivity was measured as described previously. 41 For production of supernatants, HMC-1 cells (2 ϫ 10 6 cells/mL) were cultured in the presence of 1% FCS (for stimulation of hFOB 1.19 cells) or 10% FCS (for stimulation of HMEC-1 cells and primary fibroblasts) for 24 hours.…”

Section: [ 3 H]thymidine Incorporation Assaymentioning

confidence: 99%

Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

Hoermann

Cerny-Reiterer

Perné

et al. 2011

The American Journal of Pathology

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Systemic mastocytosis is a neoplastic disease of mast cells harboring the activating KIT mutation D816V. In most patients, mast cell infiltration in the bone marrow is accompanied by marked microenvironment alterations, including increased angiogenesis, osteosclerosis, and sometimes fibrosis. Little is known about the mast cell-derived molecules contributing to these bone marrow alterations. We show here that neoplastic mast cells in patients with systemic mastocytosis express oncostatin M (OSM), a profibrogenic and angiogenic modulator. To study the regulation of OSM expression, KIT D816V was inducibly expressed in Ba/F3 cells and was found to up-regulate OSM mRNA and protein levels, suggesting that OSM is a KIT D816V-dependent mediator. Correspondingly, KIT D816V ؉ HMC-1.

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“…Furthermore, Mayerhofer et al (18) found that Hsp32/HO-1-targeting drugs suppressed the growth of primary leukemic cells obtained from patients with IM-resistant CML, including one patient carrying the T315I mutant of BCR/ABL in neoplastic cells.…”

Section: Chronic Myeloid Leukemia (Cml)mentioning

confidence: 99%

Induction of Heme Oxygenase-1 by Na+-H+ Exchanger 1 Protein Plays a Crucial Role in Imatinib-resistant Chronic Myeloid Leukemia Cells

Fang

Wang

et al. 2015

Journal of Biological Chemistry

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Background:Resistance toward imatinib (IM) hinders the treatment of advanced stage chronic myeloid leukemia (CML). Results: Induction of HO-1 contributed to the survival of K562R cells and IM-insensitive CML patients' cells during IM exposure. Conclusion: HO-1 had anti-apoptotic effects on IM-resistant CML cells. Significance: Inducing HO-1 expression via the PKC-␤/p38-MAPK pathway may promote tumor resistance to oxidative stress.

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Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib

Cited by 87 publications

References 57 publications

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

Induction of Heme Oxygenase-1 by Na+-H+ Exchanger 1 Protein Plays a Crucial Role in Imatinib-resistant Chronic Myeloid Leukemia Cells

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