Novel Faces of Heme Oxygenase-1: Mechanisms and Therapeutic Potentials

Abstract

Not only double, Janus face, but numerous appearances characterize heme oxygenase-1 (HO-1), an inducible enzyme which main role is to degrade heme. Recently, the noncanonical functions of HO-1 have particularly attracted researchers' attention. Indeed, understanding the enzyme-independent activities of HO-1 can provide additional chances for translational application of research on HO-1. In this Forum, eight reviews and two original articles describe a plethora of mechanisms in which this pleiotropic protein is involved. Further understanding of HO-1 functions is of particular significance for elucidating the pathology of various human diseases and providing rationale for novel therapies. Antioxid. Redox Signal. 20, 1673Signal. 20, -1676 S ince the discovery of heme oxygenase in 1967, the understanding of this very important enzymatic pathway in mammals has increased enormously. Majority of research concerns the inducible form, heme oxygenase-1 (HO-1), encoded by the Hmox-1 gene, and covers areas related to probably all physiological and pathological conditions. The animal models of Hmox-1 knockout reflect, although not completely, the conditions found in two described, so far, cases of humans devoid of functional Hmox-1 alleles. The effect of HO-1 deficiency is significant, both in humans and mice, and this additionally proves the importance of this enzyme. However, data in recent years accumulate, indicating that the functions of HO-1 extend beyond the effect directly related to heme degradation. The noncanonical roles of HO-1 have been addressed in numerous reviews published on that subject. However, the time is ready for new synthesis and the present Forum aims to discuss several aspects of HO-1, which have not been addressed in other articles.This Forum consists of eight reviews and two original articles. Both classical functions of HO-1 are addressed, as well as the new ones, particularly related to the role of HO-1 in stem cell differentiation and the novel molecular mechanisms, involving the HO-1 effect on microRNAs.The classical function of HO-1 is to degrade heme. This aspect is discussed and elaborated from different perspectives in the review written by Gozzelino and Soares (4). The authors concentrate on iron, one of the three products of HO-1 activity. Iron is a very reactive molecule, therefore its binding to the porphyrin ring in the form of iron protoporphyrin-heme, is the first way to prevent iron cytotoxicity. More than 80% of bioavailable iron in the cell is bound in this way. However, this solution is not permanent, heme proteins are degraded, and heme is released. Iron in Fenton reaction can generate noxious hydroxyl radicals. Not surprisingly, the next series of mechanisms has evolved, helping to eliminate iron from the cells or binding it to another protein-ferritin. The review by Gozzelino and Soares (4) elaborates particularly on one of the special functions of ferritin, which is the regulation of immune responses.As mentioned, the importance of HO-1 goes beyond its enzymatic f...

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

“…HO-1 effect is complex due to the multiple products of its activity, the non-canonical actions of the protein and the plethora of interactions of the products and protein with other pathways [141]. [90] and Ahmad et al [64].…”

HO-1 Interactors Involved in the Colonization of the Bone Niche: Role of ANXA2 in Prostate Cancer Progression

“…Taking into account the involvement of HO-1 in PCa demonstrated by us and other authors [11,16,42,43], we were keen to identify HO-1 molecular partners responsible for the biological effects provoked by HO-1 induction in prostate tumorigenesis. The literature reflects controversial results regarding the role of HO-1 in carcinogenesis [7]. Some evidence suggests that HO-1 can act as a protective enzyme, decreasing the risk of developing certain tumors.…”

“…Conclusions: ANXA2/HO-1 rises as a critical axis in PCa.Biomolecules 2020, 10, 467 2 of 24 microenvironment communicate and interact with each other to develop a fertile niche for the promotion of the metastatic process [3][4][5].Evidence has recognized inflammation as a risk factor for this neoplastic disease [6]. Heme oxygenase 1 (HO-1), encoded by the HMOX1 gene, is a stress response protein and a critical mediator of cellular homeostasis [7]. Although the role of HO-1 in cancer is controversial [8,9], we have shown that its pharmacologic or genetic upregulation is associated with a less aggressive phenotype in PCa [10].…”

“…Evidence has recognized inflammation as a risk factor for this neoplastic disease [6]. Heme oxygenase 1 (HO-1), encoded by the HMOX1 gene, is a stress response protein and a critical mediator of cellular homeostasis [7]. Although the role of HO-1 in cancer is controversial [8,9], we have shown that its pharmacologic or genetic upregulation is associated with a less aggressive phenotype in PCa [10].…”

Heme oxygenase 1 governs the cytoskeleton at filopodia: pulling the brakes on the migratory capacity of prostate tumoral cells

“…6 HO-1 is also implicated in the modulation of cellular adhesion in PCa, upregulating E-cadherin and β -catenin expression, and relocating them to the cell membrane, 7 favoring a more epithelial phenotype. However, it is yet unclear which are the HO-1 interactors and how they cooperate in the regulation of the cytoskeleton organization.…”