Abstract
Ferritin is a nanocage protein composed by the variable assembly of 24 heavy and light subunits. As major intracellular iron storage protein, ferritin has been studied for many years in the context of iron metabolism. However, recent evidences have highlighted its role, in particular that of the heavy subunit (FHC), in pathways related to cancer development and progression, such as cell proliferation, growth suppressor evasion, cell death inhibition, and angiogenesis. At least partly, the involvement in these pathways is due to the ability of FHC to control the expression of a repertoire of oncogenes and oncomiRNAs. Moreover, the existence of a feedback loop between FHC and the tumor suppressor p53 has been demonstrated in different cell types. Here, we show that ectopic over-expression of FHC induces the promoter hypermethylation and the down-regulation of miR-125b that, in turn, enhances p53 protein expression in non-small cell lung cancer (NSCLC) cell lines. Notably, analysis by absolute quantitative RT-PCR of FHC, miR-125b, and p53 strongly suggests that this axis might be active in human NSCLC tissue specimens. In vitro, FHC over-expression attenuates survival of NSCLC cells by inducing p53-mediated intrinsic apoptosis that is partially abrogated upon miR-125b re-expression. Overall, our findings demonstrate that FHC acts as a tumor suppressor gene, thus providing a potential molecular strategy for induction of NSCLC apoptotic cell death.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide
P53 activities that impact on tumor suppression extend far beyond its role in promoting cell cycle arrest or apoptosis and include the capacity to modulate glucose and lipid metabolism as well as the redox status of the cell[5,6,7,8]; p53 is considered a central hub of multiple biochemical pathways essential for the cellular homeostasis and survival
It has been demonstrated that iron depletion up-regulates p53 at post-transcriptional level[33], as well as that heme is able to bind p53 and to down-regulate its activity, by modifying localization and stability34. p53 is able, for its part, to modulate the intracellular iron homeostasis: this observation stems from the discovery that ISCU belongs to the family of p53 target genes, being provided with an intronic p53-binding site
Summary
Lung cancer is the leading cause of cancer mortality worldwide. It is a complex and heterogeneous group of diseases among which the non-small cell lung carcinoma (NSCLC) accounts for approximately 75–85% of all cases[1,2]. The complex molecular pathogenesis of NSCLC involves the activation of growth-promoting proteins (KRAS, MEK-1, EGFR, BRAF, etc.) as well as the inhibition of tumor suppressor genes (p53, PTEN, etc.)[3,4]. The tumor suppressor protein p53 is frequently deleted or mutated in a large number of lung cancer cell lines leading to the deregulation of its downstream pathways[4]. As there are many pathways downstream of p53, so they are those upstream, being the tumor suppressor activated by a variety of stress signals including irradiation, DNA damage, oncogene expression, nutrient deprivation, and hypoxia[9,10]
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