Abstract
Recent data have indicated a fundamental role of iron in mediating a non-apoptotic and non-necrotic oxidative form of programmed cell death termed ferroptosis that requires abundant cytosolic free labile iron to promote membrane lipid peroxidation. Different scavenger molecules and detoxifying enzymes, such as glutathione (GSH) and glutathione peroxidase 4 (GPX4), have been shown to overwhelm or exacerbate ferroptosis depending on their expression magnitude. Ferroptosis is emerging as a potential weapon against tumor growth since it has been shown to potentiate cell death in some malignancies. However, this mechanism has been poorly studied in Rhabdomyosarcoma (RMS), a myogenic tumor affecting childhood and adolescence. One of the main drivers of RMS genesis is the Retrovirus Associated DNA Sequences/Extracellular signal Regulated Kinases (RAS/ERK)signaling pathway, the deliberate activation of which correlates with tumor aggressiveness and oxidative stress levels. Since recent studies have indicated that treatment with oxidative inducers can significantly halt RMS tumor progression, in this review we covered different aspects, ranging from iron metabolism in carcinogenesis and tumor growth, to mechanisms of iron-mediated cell death, to highlight the potential role of ferroptosis in counteracting RMS growth.
Highlights
Iron is the most abundant heavy metal in mammals, as it is involved in a number of biological processes, ranging from metabolism and oxygen transport to DNA synthesis and antioxidant defense
Often tumor cells show a marked alteration in metabolism leading to intracellular accumulation of iron, which is strongly utilized for tumor growth and angiogenesis [1]
Schott et al found that lentiviral infection of mutated hyperactive retrovirus-associated DNA sequences (RAS) forms (NRASG12V, KRASG12V and HRASG12V) in the RMS13 cell line significantly protected against ferroptosis induced by erastin, RSL3 and auranofin, suggesting that activation of the Retrovirus Associated DNA Sequences/Extracellular signal Regulated Kinases (RAS/ERK) pathway may confer protection against oxidative stress [104]
Summary
Iron is the most abundant heavy metal in mammals (about 3–5 g in human adults), as it is involved in a number of biological processes, ranging from metabolism and oxygen transport to DNA synthesis and antioxidant defense. Often tumor cells show a marked alteration in metabolism leading to intracellular accumulation of iron, which is strongly utilized for tumor growth and angiogenesis [1]. An iron-dependent type of programmed cell death has been identified, named ferroptosis [6,7,8]. The use of ferroptosis as a weapon against tumors is of increasing interest, as tumor cells traditionally exhibit high endogenous oxidative stress levels due to gene aberrations promoting continuous cell cycles (gain of RAS, and myelocytomatosis viral related oncogene MYC) and resistance to cell senescence (P53 loss) [10]. IInn hhuummaannss,,iirroonnhhoommeeoossttaassiissiissuunnddeerrtthheeccoonnttrroollooffmmeecchhaanniissmmsstthhaattccoooorrddiinnaatteetthheeaabbssoorrppttiioonn,, eexxppoorrtt,, ssttoorraaggee,, ttrraannssppoorrtt aanndd uuttiilliizzaattiioonn ooff iron. Iron responsive protein-2 controls the transcription of TfR1, Ferritin and FPN Metallothionein-1 binds heavy metals. Pathway controlling the biosynthesis of selenoproteins, such as GPX4 Iron-storage protein
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