A Dual Role of Heme Oxygenase-1 in Cancer Cells

Abstract

Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors.

Keywords: chemotherapy; ferroptosis; glutathione; heme oxygenase-1; iron; reactive oxygen species.

Figure 1

Heme metabolism. Heme is degraded by heme oxygenase (HO), leading to the generation of biliverdin, carbon monoxide, and ferrous iron. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under most conditions, biliverdin and bilirubin act as anti-oxidants by scavenging or neutralizing reactive oxygen species (ROS). Carbon monoxide, a gaseous product, mainly functions in signaling transduction, including the vasodilation of blood vessels, production of anti-inflammatory cytokines, upregulation of anti-apoptotic effectors, and thrombosis. Ferrous iron is the major pro-oxidant in all metabolites of heme. However, heme oxygenase-1 (HO-1) activation also increases ferritin expression, which can bind to ferrous iron and detoxify its pro-oxidant effect. The black arrows indicate that biliverdin metabolize into bilirubin. The dotted arrow indicates that carbon monoxide serves a regulator in vasodilatory, anti-inflammatory, anti-apoptotic, anti-thromobtic, and angiogenesis activities. The dotted arrow below iron indicates the iron increase will increase ferritin, which neutralizes the pro-oxidant effect of iron.

Figure 2

Scheme of HO-1-regulated ferroptosis. HO-1 plays a dual role in ferroptosis, pro-ferroptotic and anti-ferroptotic effects. Erastin and sorafenib (xCT inhibitor) and RSL3 (glutathione peroxidase 4 (GPx4) inhibitor) can deplete glutathione, leading to ROS generation. In response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) disassociates from Kelch-like ECH-associated protein 1 (Keap1), and then migrates into nuclei, where it binds the antioxidant-response element (ARE) site of target genes such as HO-1 and ferritin. HO-1 catalyzes heme degradation to generate ferrous iron (Fe²⁺). Ferrous iron is highly reactive as a pro-oxidant and, thus, produces ROS. Excessive ROS damage intracellular structures and DNA, causing the peroxidation of lipid and protein and eventually cell death. Nrf2 induces ferritin expression to chelate ferrous iron, avoiding ROS overload. Recently, some small molecules were identified to possess a pro-ferroptosis effect through HO-1. Heme can directly activate HO-1 expression. Similar to erastin and sorafenib, BAY117089 can deplete GSH and increase ROS production, resulting in Nrf2−HO-1 activation and ferroptosis. Withaferin A directly targets Keap1 and releases Nrf2, followed by HO-1 activation, iron accumulation, and cell death. Magnesium isoglycyrrhizinate (MgIG) increases HO-1 expression and free cellular iron level. By contrast, the activation of HO-1 might provide a cytoprotective effect. For example, in erastin-, sorafenib-, and RSL-stimulated cells, ferritin expression is increased through the Nrf2−HO-1 pathway and neutralize iron toxicity. Nrf2-targeted antioxidant gene expression also benefits the acquisition of drug resistance. Artesunate also induces the Nrf2−HO-1 signal to assist cells to acquire drug resistance.

Figure 3

Model of HO-1-mediated ferroptosis. HO-1 exerts a cytoprotective effect by scavenging ROS during moderate activation. By contrast, excessive activation of HO-1 increases labile Fe²⁺, leading to ROS overload and death of cancer cells.