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.
Highlights
The heme oxygenase (HO) family of enzymes serve as the rate-limiting step in the degradation of heme which is released by dying cells and yields the biologically active catabolites biliverdin, ferrous iron (Fe2+) and carbon monoxide (CO) [1]
It is clear that in some cases the biological landscape of the specific tumor microenvironment (TME) may play a role in dictating the overall outcome of pharmacologically targeting Heme oxygenase-1 (HO-1) which can be dependent on the quality of the antitumor immune response and the degree of T-cell infiltration into the TME [2, 26]
The observation that in malignant tumor cells, HO-1 can become truncated and localized to the nucleus to elicit a transcriptional-regulatory role provides an intriguing additional layer to the functionality of this protein, but highlights the need to consider the cellular localization of HO1 rather than just its presence or absence in the TME [11, 16, 23, 44]
Summary
The heme oxygenase (HO) family of enzymes serve as the rate-limiting step in the degradation of heme which is released by dying cells and yields the biologically active catabolites biliverdin, ferrous iron (Fe2+) and carbon monoxide (CO) [1]. The catabolites of heme degradation can 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.
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