NCOA4 Controls iron-dependent cell proliferation and death
Abstract
NCOA4 protein mediates autophagic degradation of ferritin to maintain intracellular iron concentration and inhibits DNA replication origin activation via hindrance of the MCM2-7 DNA helicase. In iron deficiency, NCOA4 inhibits DNA replication to prevent replication stress, genome instability and cell death. On the other hand, NCOA4-mediated ferritinophagy is necessary to supply iron for propagation of lipid oxidation during ferroptosis induction. Thus, NCOA4 protein levels increase upon treatment with several ferroptosis inducers and NCOA4-interfered cells display resistance to ferroptosis. We will discuss the signalling pathways and molecular mechanisms that promote NCOA4-mediated ferritinophagy upon induction of ferroptosis.
Biosketch
I have a long-lasting interest in studying the molecular basis of human diseases. During beginning of my carrier, I have dedicated my attention to study the effect of RET mutations both in cancer as well as in developmental disorders such as congenital megacolon or Hirschsprung disease. (Santoro, Carlomagno et al, 1992; Santoro, Carlomagno et al, 1995; Carlomagno et al, 1995; Carlomagno et al, 1997; Carlomagno et al, 1998,). Subsequently during my second post-doc I have identified RET kinase inhibitors to be used in cancer treatment and mechanism of resistance to such inhibitors (Carlomagno et al, 2002, Carlomagno et al, 2003, Carlomagno, 2004, Carlomagno 2006, Guidaand Carlomagno, 2008, ect). The approval of vantetanib, the first kinase inhibitor for the treatment of Medullary Thyroid Carcinoma that frequently displays RET oncogenic conversion, stemmed from our observation vandetanib is able to block RET kinase activity (Carlomagno, 2002). I have kept collaborating with my former lab and with prof. Hong-yu Li from San Antonio University, in identifying additional RET and TRKs inhibitors (Frett, 2014; Frett, 2015; Moccia M, 2020; Moccia M, 2021; Yan, 2021; Zhang, 2022). In 2007 I started my lab working on NCOA4 protein and identifying its role in controlling DNA replication and iron metabolism (Bellelli et al, 2014, Bellelli et al, 2016, Federico et al 2022). Thereby in these last 15 years my interest has moved to diseased featuring alteration of iron homeostasis and erythropoiesis (Mattè et al 2018, Nai et al 2019, Mattè et al 2021, Nai et al 2021).
