Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway

Kwok, Simon C. M.

doi:10.1155/2013/162094

Cited by 19 publications

(9 citation statements)

References 35 publications

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“…ZnPP by itself did not induce HMOX1 expression (Figure 8B ). However, when combined with ATO, ZnPP had a dual effect: 1) it potentiated the increase on HMOX1 expression induced by ATO, in agreement with the reported role of ZnPP as an inducer of HMOX1 and an inhibitor of its activity [ 33 , 34 ]; 2) it affected HMOX1 mobility in gels, suggesting that besides inhibiting HMOX1 activity, ZnPP binding induced a conformational change in HMOX1, further confirming the activity of this compound (Figure 8B ).…”

Section: Resultssupporting

confidence: 86%

Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9

et al. 2016

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CLL remains an incurable disease in spite of the many new compounds being tested. Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could constitute an efficient therapy. To further explore this, we have studied the gene expression profile induced by ATO in CLL cells. ATO modulated many genes, largely involved in oxidative stress, being HMOX1 the most upregulated gene, also induced at the protein level. ATO also increased MMP-9, as we previously observed, both at the mRNA and protein level. Using specific inhibitors, qPCR analyses, and gene silencing approaches we demonstrate that upregulation of MMP-9 by ATO involved activation of the p38 MAPK/AP-1 signaling pathway. Moreover, gene silencing HMOX1 or inhibiting HMOX1 activity enhanced p38 MAPK phosphorylation and c-jun expression/activation, resulting in transcriptional upregulation of MMP-9. Overexpression of HMOX1 or enhancement of its activity, had the opposite effect. Cell viability analyses upon modulation of HMOX1 expression or activity demonstrated that HMOX1 had a pro-apoptotic role and enhanced the cytotoxic effect of ATO in CLL cells. We have therefore identified a new mechanism in which HMOX1 plays a central role in the response of CLL cells to ATO and in the regulation of the anti-apoptotic protein MMP-9. Thus, HMOX1 arises as a new therapeutic target in CLL and the combination of HMOX1 modulators with ATO may constitute an efficient therapeutic strategy in CLL.

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Section: Resultssupporting

confidence: 86%

Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9

et al. 2016

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“…MPs not only inhibit the activity of both isoenzymes of HO [ 86 ] but because of the similarity of structure to heme, most of them also affect other heme-dependent enzymes like nitric oxide synthases (NOS), soluble guanylyl cyclase (sGC) or cytochromes P450 (CYPs) [ 87 , 88 ]. Paradoxically, they also induce HO-1 on mRNA and protein level [ 9 , 89 , 90 , 91 ]. These wide-ranging actions cause potential concerns in the interpretation of effects ascribed to MPs.…”

Section: Pharmacological Inhibition Of Ho-1 Activitymentioning

confidence: 99%

Heme oxygenase inhibition in cancers: possible tools and targets

Podkalicka¹,

Mucha²,

Józkowicz³

et al. 2018

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Heme oxygenase-1 (HO-1, encoded by HMOX1) through degradation of pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe2+) and biliverdin, exhibits cytoprotective, anti-apoptotic and anti-inflammatory properties. All of these potentially beneficial functions of HO-1 may play an important role in tumors’ development and progression. Moreover, HO-1 is very often upregulated in tumors in comparison to healthy tissues, and its expression is further induced upon chemo-, radio- and photodynamic therapy, what results in decreased effectiveness of the treatment. Consequently, HO-1 can be proposed as a therapeutic target for anticancer treatment in many types of tumors. Nonetheless, possibilities of specific inhibition of HO-1 are strongly limited. Metalloporphyrins are widely used in in vitro studies, however, they are unselective and may exert serious side effects including an increase in HMOX1 mRNA level. On the other hand, detailed information about pharmacokinetics and biodistribution of imidazole-dioxolane derivatives, other potential inhibitors, is lacking. The genetic inhibition of HO-1 by RNA interference (RNAi) or CRISPR/Cas9 approaches provides the possibility to specifically target HO-1; however, the potential therapeutic application of those methods are distant at best. In summary, HO-1 inhibition might be the valuable anticancer approach, however, the ideal strategy for HO-1 targeting requires further studies.

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“…Recently, the heme oxygenase/carbon monoxide (HO/CO) system has attracted a great deal of attention. HO-1, which has constitutive and inducible isoforms ( 6 , 7 ), catalyzes the rate-limiting step in the oxidative degradation of heme to biliverdin ( 8 ), releasing equimolar quantities of CO and iron ( 9 ). Previous studies have shown that hepatic HO-1 was overexpressed in cirrhotic rats ( 10 ) and contributed to portal hypertension ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Guo

Duan

et al. 2014

Molecular Medicine Reports

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The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase-1 (HO-1) expression, together with the influence of altered hepatic HO-1 expression levels on hepatic function and fibrosis in bile duct-ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO-1 mRNA were measured by reverse-transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson’s staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO-1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide-treated group exhibited significantly reduced hepatic HO-1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO-1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO-1 overexpression in cirrhotic rats, reduced hepatic HO-1 expression levels to relieve liver injury and attenuated liver fibrosis.

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Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway

Cited by 19 publications

References 35 publications

Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9

Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9

Heme oxygenase inhibition in cancers: possible tools and targets

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

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