Iron as spirit of life to share under monopoly

Abstract

Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multisystem organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

Environmental impact on carcinogenesis under BRCA1 haploinsufficiency

“…We have been working on iron-induced carcinogenesis for decades. Among them, repeated intraperitoneal injections of ferric nitrilotriacetate (Fe-NTA) induces renal cell carcinoma (RCC) in a high incidence (60 ~ 90%) in male rats [9,12]. In this model, renal tubular necrosis is observed as early as 30 min in the proximal tubular cells with various lipid peroxidation products [43][44][45][46], which are the observation of our own in the 1980's and 1990's.…”

“…This is further based on our own observation and observation by other investigators that 1) excess iron in various human pathology is associated with higher risk for carcinogenesis [7][8][9]; 2) iron reduction by phlebotomy decreases the cancer risk and mortality in a human intervention study [10]; 3) repeated iron-catalyzed Fenton reaction causes aggressive cancer that is similar to human counterparts not only in macroscopic/microscopic morphology but also in genetic alterations [11,12]. These animal models include ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis [12][13][14][15] and asbestos-induced mesothelial carcinogenesis in rats [16][17][18][19]; 4) especially in the latter case, iron removal by iron chelating agent [20] or phlebotomy [21] can prevent mesothelial carcinogenesis to some extent. More detailed review on these topics are found elsewhere [9,12,22].…”

“…When we first recognized the word ferroptosis in 2014, we immediately accepted it, based on our experience of this oxidative renal tubular damage. In the Fe-NTA-induced renal carcinogenesis model, renal tubular cells obtain ferroptosis-resistance in a few weeks after continued iron-catalyzed oxidative stress [12,47,48]. We have been proposing a hypothesis that carcinogenesis is a process to acquire ferroptosis-resistance under iron addiction via somatic mutation(s) [4].…”

“…We have recently applied Fe-NTA renal carcinogenesis model to male Brca1(L63X/ +) rats to evaluate whether iron-catalyzed oxidative stress [12] is important for Brca1 mutant carcinogenesis [83]. The incidence of renal carcinogenesis was not changed between the Brca1 mutant and the wild-type.…”

“…These animal models include ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis [12][13][14][15] and asbestos-induced mesothelial carcinogenesis in rats [16][17][18][19]; 4) especially in the latter case, iron removal by iron chelating agent [20] or phlebotomy [21] can prevent mesothelial carcinogenesis to some extent. More detailed review on these topics are found elsewhere [9,12,22]. At first, we here describe the recent advances in iron metabolism in mammals, including the concept of ferroptosis.…”