Heme Oxygenase-1 in Tumors: Is It a False Friend?

Abstract

Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to biologically active products: carbon monoxide (CO), biliverdin, and ferrous iron. It participates in maintaining cellular homeostasis and plays an important protective role in the tissues by reducing oxidative injury, attenuating the inflammatory response, inhibiting cell apoptosis, and regulating cell proliferation. HO-1 is also an important proangiogenic mediator. Most studies have focused on the role of HO-1 in cardiovascular diseases, in which its significant, beneficial activity is well recognized. A growing body of evidence indicates, however, that HO-1 activation may play a role in carcinogenesis and can potently influence the growth and metastasis of tumors. HO-1 is very often upregulated in tumor tissues, and its expression is further increased in response to therapies. Although the exact effect can be tissue specific, HO-1 can be regarded as an enzyme facilitating tumor progression. Accordingly, inhibition of HO-1 can be suggested as a potential therapeutic approach sensitizing tumors to radiation, chemotherapy, or photodynamic therapy. HEME OXYGENASE-1 (HO-1)HEME OXYGENASE (HO) is a microsomal enzyme catalyzing the first, rate-limiting step in degradation of heme and playing an important role in recycling of iron (103). It cleaves the α-meso carbon bridge of heme, yielding equimolar quantities of carbon monoxide (CO) and iron ions Fe 2+ and biliverdin (156). CO is then exhaled from the organisms through the lung (50). Free iron induces the expression of the iron-sequestering ferritin and activates FeATPase, an iron transporter, which decrease intracellular Fe 2+ content. Finally, biliverdin is converted by biliverdin reductase to bilirubin (144), which can be oxidized by cytochrome P450 enzymes, such as Cyp1A1, Cyp2B1, or Cyp2a5, or glucoronidated by UDPglucuronyl-transferase and subsequently eliminated as bilirubin glucoronides by the biliaryfecal pathway (25).The enzymatic activity of HO results in decreased oxidative stress, attenuated inflammatory response, and a lower rate of apoptosis (Fig. 1). This is due to removal of heme, a potent prooxidant and proinflammatory agent, but also because of generation of biologically active products. Among them, CO is an important cellular messenger, with the signaling function resembling that of nitric oxide (NO). Like NO, CO induces soluble guanylyl cyclase (sGC) and thereby inhibits platelet aggregation, decreases leukocyte adhesion, and reduces endothelial cell apoptosis. In addition, it exerts antiinflammatory effects by inhibition of tumor necrosis factor (TNF), interleukin-1β (IL-1β), and macrophage inflammatory protein-1β (MIP-1β), or by upregulation of interleukin-10 (IL-10) (123). Ferrous iron, the © Mary Ann Liebert, Inc. Address reprint requests to: Alicja Jozkowicz, Ph.D., D.Sc., Department of Medical Biotechnology, Faculty of Biophysics, Biochemistry and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland, E-mail:alicia@mol.uj.edu.pl. Europe PMC Funders Gr...

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

“…HO-1 is an antiapoptotic gene product that is overexpressed in cancers (Jozkowicz et al, 2007), and expectedly, lack of HO-1 has been shown to lead to sensitization of cells to death (Fang et al, 2004;ChenRoetling et al, 2005;Jozkowicz et al, 2007). Consistently, cells lacking p53 and hence expressing reduced HO-1 are also more susceptible to death, and silencing HO-1 expression promotes cells death upon H 2 O 2 treatment only in p53-proficient cells (this report), indicating that HO-1 is indeed a target of p53 that is responsible for p53-dependent cellular survival, although probably not the only.…”

“…HO-1 with its antioxidant, antiapoptotic and proangiogenic properties has been shown to be overexpressed in cancers (Ferris et al, 1999;Petrache et al, 2000;Jozkowicz et al, 2007;Gozzelino et al, 2010). It regulates cellular homeostasis and protects against cellular and tissue injury, and consistently, HO-1-deficient mice were found to be significantly more susceptible to tissue injury than their wild-type counterparts (Chen-Roetling et al, 2005).…”

Increased levels of plasma haemoxygenase-1 in prostate cancer

“…However, possible roles in different pathophysiology patterns are emerging, such as protection of the endothelium from oxidative stress. 4,6,7 HO-1 may also be important in cardiovascular disease and in apoptosis, 5,9,19,20 and there is also evidence that HO-1 may be linked experimentally to angiogenesis via VEGF. [10][11][12]18,21 It is therefore notable that we report good correlations between HO-1 and VEGF (r40.52) (although we acknowledge the possibility of small number error) in the absence of cancer, but that this correlation in markedly weaker in the presence of cancer (r ¼ 0.12).…”

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

“…PDT induced p38 activation has by others also been associated with induction of VEGF using both BPD and Hypericin as photosensitizers (Hendrickx et al 2005, Solban et al 2006) and activation of p38 after hypericin PDT is in addition shown to upregulate cyclooxygenase-2 (Hendrickx et al 2003) and heme-oxygenase 1 (Kocanova et al 2007). Induction of both VEGF (Ferrara & Gerber 2001, Kowanetz & Ferrara 2006, COX-2 (Bakhle 2001) and heme-oxygenase (Jozkowicz et al 2007 Protein NuTu-19 WiDr A-431 p-EGFR decrease no effect no effect EGFR no effect no effect no effect p-ERK increase increase decrease ERK no effect no effect no effect p-JNK increase not detected not detected JNK no effect no effect no effect p-p38 increase increase increase P38 no effect no effect no effect Protein NuTu-19 A-431 p-EGFR decrease decrease EGFR decrease no effect p-ERK increase -ERK no effect -p-JNK --JNK no effect -p-p38 increase -P38 no effect - …”