Heme Oxygenase-1 in Tumor Biology and Therapy

Heme oxygenase-1 (HO-1) degrades heme to carbon monoxide (CO), biliverdin, and ferrous iron. As HO-1 expression is highly increased by stressful conditions, the major role of the enzyme is the protection against oxidative injury. Additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis. Beneficial activities of HO-1 have been recognized in many pathological states e.g. atherosclerosis, diabetes, ischemia/reperfusion injury or organ transplantation. Interestingly HO-1 expression is very often boosted in tumor tissues and could be further elevated in response to radio-, chemo-, or photodynamic therapy. A growing body of evidence suggests that HO-1 may play a role in tumor induction and can potently improve the growth and spread of tumors. This review discusses the implications of HO-1 properties for tumor proliferation and cell death, differentiation, angiogenesis and metastasis, and tumor-related inflammation. Finally, it suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies. Keywords: Heme oxygenase-1, carcinogenesis, oxidative stress, cytoprotection, angiogenesis, metastasis, carbon monoxide (CO), biliverdin, ferrous iron, oxidative injury, atherosclerosis, diabetes, ischemia/reperfusion injury, photodynamic therapy, anticancer therapies, aneuploidy, malignancy, heterozygosity, serine/threonine kinases, Oncogenes, Tumor-associated angiogenic factors, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), reactive oxygen species (ROS), cytotoxicity, apoptotic/necrotic cell death, superoxide dismutase (SOD), biliverdin reductase (BvR), glucoronidated, UDPglucuronyl transferase, Purkinje cells, cerebellum, ferriporphyrins, ferrohemoglobin, hemopexin, haptoglobin, soluble guanylyl cyclase (sGC), tumor necrosis factor (TNF), interleukin-1β (IL-1β), macrophage inflammatory protein-1β (MIP-1β), lymphosarcoma, Kaposi sarcoma, viral G protein-coupled receptor (vGPCR), namely a-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), hepatocarcinogenesis, Squamous carcinoma, human gliomas, hormonerefractory prostate cancer (HRPCA), localized prostate cancer (PCA), activator protein-1 (AP-1), TUMOR CELL PROLIFERATION, mesoporphyrin-IX, cobalt protoporphyrin-IX (CoPPIX), cyclin-dependent kinase (Cdk), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), Sp1 (Stimulatory protein-1), vascular smooth muscle cells (VSMC), retinoblastoma protein (Rb), desferroxamine (DFO), mesenchymal stem cells (MSC), dimethyl sulfoxide (DMSO), haematopoietic, endothelial progenitor cells (EPC), APOPTOSIS, ZnPPIX-poly ZnPPIX-polyethylene, glycol (ZnPPIX-PEG), epigallocatechin 3-gallate (EGCG), anticancerogenic polyphenol, iron regulatory proteins (IRP1, transferrin receptor (TfR), astroglia, myelogenous leukemia cells, keratinocytes, matrix metalloproteinase-1 (MMP-1), thymidyne phosphorylase (TP), stroma cell-derived growth factor-1 (SDF-1), splenomegaly, lymphadenopathy, lipopolysaccharide (LPS), c-Jun N-terminal kinase, colony, –, stimulating factor (GMCSF), toll-like receptor-4 (TLR4), oral squamous cell carcinoma (OSCC), tin mesoporphyrin-IX (SnMPIX, telomerase reverse transcriptase (TERT)