Abstract
Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.
Highlights
Heme oxygenase (HO) is an evolutionarily conserved enzyme that, in the presence of molecular oxygen (O2 ) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), catalyzes the degradation of heme into equimolar amounts of biliverdin, carbon monoxide (CO), and free iron (Fe2+ ), releasing NADP+ and H2 O [1].Two different isoforms of HO have been described in mammalian cells (HO-1 and HO-2) and, heme oxygenase 1 (HO-1) represents the inducible form [2]
HO-1-derived free iron induces the synthesis of the heavy chain of the iron-chelating protein ferritin and activates the membrane transporter Fe-ATPase, which is crucial for decreasing the intracellular concentration of free Fe2+ and for preventing reactive oxygen species (ROS) production through the Fenton reaction [44,45]
PI3K/AKT has been proved to be involved in HO-1 induction in SHSY5Y neuroblastoma cancer cells in response to guanosine [75] and in cholangiocarcinoma cells treated with piperlongumine [76]
Summary
Heme oxygenase (HO) is an evolutionarily conserved enzyme that, in the presence of molecular oxygen (O2 ) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), catalyzes the degradation of heme into equimolar amounts of biliverdin, carbon monoxide (CO), and free iron (Fe2+ ), releasing NADP+ and H2 O [1]. HO-1-derived free iron induces the synthesis of the heavy chain of the iron-chelating protein ferritin and activates the membrane transporter Fe-ATPase, which is crucial for decreasing the intracellular concentration of free Fe2+ and for preventing ROS production through the Fenton reaction [44,45]. HO-1 overactivation, if not balanced by the induction of ferritin and iron transporters or quenching systems, can trigger ferroptosis In this condition, iron accumulation leads to cell death through excessive ROS production and consequent lipid peroxidation [46,47]. Among HO-1 metabolic products, only CO has been recognized to be directly involved in tumor progression, promoting cancer cell proliferation, migration, angiogenesis, and immune escape [11]. This review touches on the relevance of HO-1 expression in cancer progression, with a particular interest in the correlation with clinical features of tumors, taking into account data from histopathological analysis of tumor specimens
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