Heme Oxygenase-1 and Prostate Cancer: Function, Regulation, and Implication in Cancer Therapy

Abstract

Prostate cancer (PC) is a significant cause of mortality in men worldwide, hence the need for a comprehensive understanding of the molecular mechanisms underlying its progression and resistance to treatment. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme catabolism, has emerged as a critical player in cancer biology, including PC. This review explores the multifaceted role of HO-1 in PC, encompassing its function, regulation, and implications in cancer therapy. HO-1 influences cell proliferation, anti-apoptotic pathways, angiogenesis, and the tumor microenvironment, thereby influencing tumor growth and metastasis. HO-1 has also been associated with therapy resistance, affecting response to standard treatments. Moreover, HO-1 plays a significant role in immune modulation, affecting the tumor immune microenvironment and potentially influencing therapy outcomes. Understanding the intricate balance of HO-1 in PC is vital for developing effective therapeutic strategies. This review further explores the potential of targeting HO-1 as a therapeutic approach, highlighting challenges and opportunities. Additionally, clinical implications are discussed, focusing on the prognostic value of HO-1 expression and the development of novel combined therapies to augment PC sensitivity to standard treatment strategies. Ultimately, unraveling the complexities of HO-1 in PC biology will provide critical insights into personalized treatment approaches for PC patients.

Keywords: HO-1; hypoxia; immunomodulation; metastasis; oxidative stress; prostate cancer (PC); therapeutic strategy; therapy resistance.

Figure 1

Diagnosis of PC. The diagnosis begins with the measurement of PSA levels in the blood, where elevated levels may indicate the presence of PC. If elevated PSA levels are detected, a biopsy is performed on prostate tissues, and a Gleason score is assigned to determine the aggressiveness of the disease. The biopsy results can differentiate between BPH and cancer. Tumor stage, Gleason score, and PSA levels determine the treatment strategy, which may include radical prostatectomy, hormonal therapy, radiotherapy, or chemotherapy. (Created with BioRender.com).

Figure 2

Cellular Localization and Function of HO-1. HO-1 is upregulated by various stimuli, including hypoxia, ROS, oxidative stress, and heme. HO-1 is initially synthesized and localized to the endoplasmic reticulum (ER), where it catalyzes the degradation of heme. This process produces biliverdin, which is subsequently converted to bilirubin by biliverdin reductase A (BVRA), carbon monoxide (CO), and ferrous iron (Fe²⁺). Ferrous iron is quickly sequestered into ferritin for storage. Both biliverdin and bilirubin serve as potent antioxidants, while CO exerts cytoprotective effects by activating anti-inflammatory and anti-apoptotic pathways. Under stress conditions, HO-1 undergoes proteolytic cleavage (t-HO-1) and translocates to the nucleus, where it regulates the expression of genes related to antioxidants, angiogenesis, metastasis, anti-apoptosis, and other crucial cellular processes. (Created with BioRender.com).

Figure 3

The regulation of HO-1 in PC cells. Multiple pathways regulate HO-1 expression in PC cells. The NRF2 pathway is crucial, where under oxidative stress, NRF2 dissociates from KEAP1, translocates to the nucleus, binds to ARE in the HO-1 promotor region, and activates transcription. The HIF-1α pathway also activates HO-1 transcription, under hypoxic conditions, HIF-1α translocates to the nucleus where it dimerizes with HIF-1β to form the HIF-1 complex, which binds to HREs in the HO-1 promotor. Additionally, inflammation activates NF-ƙB pathway, which translocates to the nucleus and binds the HO-1 promotor, inducing transcription. The MAPK pathway promote HO-1 expression through intermediate signaling pathways, including the activation of AP-1 transcription factor, which binds to the HO-1 promotor, inducing transcription. (Created with BioRender.com).

Figure 4

The Role of HO-1 in PC Progression. In hypoxic tumors, HIF-1α is activated, which in turn upregulates HO-1 expression. This upregulation triggers pathways that promote PC invasion, tumorigenesis, metastasis, and therapy resistance. HO-1 plays a key role in mitigating the effects of elevated ROS levels in PC cells by activating survival pathways and inhibiting apoptosis. Inhibition of HO-1 using SnPP or ZnPP results in increased ROS levels, leading to cancer cell apoptosis. Additionally, HO-1 facilitates PC metastasis by promoting angiogenesis, enhancing MMP activity, and driving EMT processes. HO-1 also exerts immunomodulatory effects, where elevated HO-1 levels are associated with the anti-inflammatory and tumor-promoting M2 phenotype. Conversely, inhibiting HO-1 activity shifts macrophage polarization towards the M1 phenotype, which is pro-inflammatory and anti-tumorigenic (arrows indicate enhancement or inhibition). (Created with BioRender.com).