An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

SIMPLE SUMMARY: Heme is an iron-containing porphyrin that functions as a prosthetic group in hemoproteins and is involved in many biological processes. This review article summarizes (1) the varied effects of heme and heme oxygenase in tumorigenesis of different cancer types; (2) the molecular mechanisms of interaction of heme with regulatory and signaling proteins implicated in tumorigenesis, such as BACH1, PGRMC1, P53, CBS, sGC, and NOS; (3) the roles of altered heme levels and metabolism in the pathogenesis of diseases, including diabetes mellitus and Alzheimer’s dementia. Understanding the effects of heme in diverse cellular processes and disease progression identifies potential therapeutic targets and provides insights for developing novel treatment strategies. ABSTRACT: Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer’s disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-β-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.