The Diverse Roles of Heme Oxygenase-1 in Tumor Progression

Abstract

Heme oxygenase-1 (HO-1) is an inducible intracellular enzyme that is expressed in response to a variety of stimuli to degrade heme, which generates the biologically active catabolites carbon monoxide (CO), biliverdin and ferrous iron (Fe2+). HO-1 is expressed across a range of cancers and has been demonstrated to promote tumor progression through a variety of mechanisms. HO-1 can be expressed in a variety of cells within the tumor microenvironment (TME), including both the malignant tumor cells as well as stromal cell populations such as macrophages, dendritic cells and regulatory T-cells. Intrinsically to the cell, HO-1 activity provides antioxidant, anti-apoptotic and cytoprotective effects via its catabolites as well as clearing toxic intracellular heme. However, the catabolites of heme degradation can also diffuse outside of the cell to extrinsically modulate the wider TME, influencing cellular functionality and biological processes which promote tumor progression, such as facilitating angiogenesis and metastasis, as well as promoting anti-inflammation and immune suppression. Pharmacological inhibition of HO-1 has been demonstrated to be a promising therapeutic approach to promote anti-tumor immune responses and inhibit metastasis. However, these biological functions might be context, TME and cell type-dependent as there is also conflicting reports for HO-1 activity facilitating anti-tumoral processes. This review will consider our current understanding of the role of HO-1 in cancer progression and as a therapeutic target in cancer.

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…HO-1 is predominantly considered a pro-tumour enzyme since it is overexpressed in a wide range of cancers and has been shown to favour tumour progression by different mechanisms [ 56 ]. This aspect will be considered in the next subparagraph.…”

HO-1 Modulates Aerobic Glycolysis through LDH in Prostate Cancer Cells

“…However, there are studies showing that HO-1 can play an opposite pro-tumoral effect in head and neck squamous cell carcinoma [ 59 ], non-small cell lung cancer [ 60 ] and gliomas [ 61 ]. This HO-1 dual role in cancer, which seems to be context, tumor microenvironment and cell type-dependent [ 62 ], could be partially explained by HO-1 subcellular localization [ 63 ] and its dependence on tissue conditions to act as a pro- or anti-angiogenic factor [ 64 , 65 ].…”

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

“…The pro-tumorigenic role of HO-1 has been reported in lung cancer, gliomas, gastrointestinal cancers, thyroid cancer, genitourinary cancers, melanoma, and hematological malignancies [17,45]. These effects of HO-1 in cancer, which are carried out via HMOX1 regulation, modulating tumor microenvironment, and translocating to the nucleus, have been thoroughly reviewed [17,44,46]. HO-1 and heme degradation product CO have been shown to induce angiogenesis in tumors, possibly through stimulation of vascular endothelial growth factor (VEGF) expression [47][48][49][50][51].…”

“…The mechanism of VEGF stimulation involving CO has been proposed to be mediated by hypoxia-inducible factor 1-alpha (HIF-1α) [53][54][55]. The activity of HO-1 may also allow cancer cells to avoid immune response via its expression both in cancer cells and in other cells in the tumor microenvironment including dendritic cells, as well as tumor associated macrophage (TAM) cells that can prevent activation of cytotoxic T cells [46,56]. HO-1 inhibits the maturation of dendritic cells, protecting tumors from T cell-based immune response [57][58][59][60].…”

“…Labile heme has been recognized as a compelling pro-inflammatory conciliator. When released from hemoglobin, labile heme can become a DAMP [46]. Heme is well-depicted as Hb-derived DAMP that targets various immune and non-immune cells.…”