Stromal cell-derived factor (SDF)-1alpha, a member of the chemokine CXC subfamily, plays an important role in regulation of a variety of cellular functions of endothelial progenitor cells such as cell migration, proliferation, survival and angiogenesis. However, there is relatively little information linking the cellular functions and individual signaling pathways mediated by SDF-1alpha in endothelial progenitor cells. In our study, we showed that endothelial progenitor cells expressed CXCR4 by reverse transcription polymerase chain reaction and flow cytometric analysis. Functional analysis showed that SDF-1alpha induced a concentration-dependent migration of endothelial progenitor cells and the migration was CXCR4 dependent as confirmed by the total inhibition by AMD3100, a CXCR4-specific peptide antagonist. The migration can also be nearly completely blocked by phosphoinositide 3-kinase inhibitors (LY294002 and wortmannin) and eNOS inhibitor (N-nitro-arginine methyl ester), whereas mitogen-activated protein kinase/ERK inhibitor (PD98059) had no significant effect on SDF-1alpha-induced migration. The treatment of endothelial progenitor cells with SDF-1alpha resulted in time and concentration-dependent Akt, eNOS, and ERK1/2 phosphorylation. These findings suggested that phosphoinositide 3-kinase/Akt/eNOS, but not mitogen-activated protein kinase/ERK, signal transduction pathway may be involved in SDF-1alpha mediated migration of endothelial progenitor cells.

Despite significant developments and persistent efforts by scientists, cancer is one of the primary causes of human death worldwide. No form of life on Earth can survive without iron, although some species can live without oxygen. Iron presents a double‐edged sword. Excess iron is a risk for carcinogenesis, while its deficiency causes anemia, leading to oxygen shortage. Every cell is eventually destined to death, either through apoptosis or necrosis. Regulated necrosis is recognized in distinct forms. Ferroptosis is defined as catalytic Fe(II)‐dependent regulated necrosis accompanied by lipid peroxidation. The main observation was necrosis of fibrosarcoma cells through inhibition of cystine/glutamate antiporter with erastin, which reduced intracellular cysteine and, thus, glutathione levels. Our current understanding of ferroptosis is relative abundance of iron (catalytic Fe[II]) in comparison with sulfur (sulfhydryls). Thus, either excess iron or sulfur deficiency causes ferroptosis. Cell proliferation inevitably requires iron for DNA synthesis and energy production. Carcinogenesis is a process toward iron addiction with ferroptosis resistance. Conversely, ferroptosis is associated with aging and neurodegeneration. Ferroptosis of immune cells during infection is advantageous for infectious agents, whereas ferroptosis resistance incubates carcinogenic soil as excess iron. Cancer cells are rich in catalytic Fe(II). Directing established cancer cells to ferroptosis is a novel strategy for discovering cancer therapies. Appropriate iron regulation could be a tactic to reduce and delay carcinogenesis.

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