p38 and ERK MAP kinase mediates iron chelator-induced apoptosis and -suppressed differentiation of immortalized and malignant human oral keratinocytes

Tuning Cell Cycle Regulation with an Iron Key

“…206 Iron and the Cell Cycle Induction of apoptosis by Dp44mT and DFO was accompanied by a decrease in Bcl-2 expression, an increase in Bax and also cytochrome c efflux from the mitochondrion. 93,169 More recently, and similarly, DFO has been shown to induce apoptosis through down-regulation of the Bcl-2 protein and upregulation of Bax in malignant oral keratinocytes. 169 It has been reported that incubation of cells with DFO leads to the nuclear accumulation of PLAGL2 which results in the expression of the pro-apoptotic factor, BNIP3.…”

“…164 Studying the effect of DFO, Lee et al showed that Fe-depletion strongly activated p38 MAPK and ERK, but did not activate JNK. 169 In addition, the selective p38 MAPK inhibitor, SB203580, and ERK inhibitor, PD98059, protected cells against Fe chelator-induced death in oral keratinocytes and cancer cells. 169 This suggests that p38 and ERK MAPKs are potential mediators of cell death induced by Fe-deprivation.…”

“…Several studies have reported that after Fe-depletion there are alterations to the level of GADD45 interacting partners, such as p38 169 and cdk2/cyclin B. 101 It can be hypothesized that GADD45 may mediate growth arrest through inhibiting the activity of cyclin B and cdk2 163 and studies have shown that Fe-depletion decreases the expression of these regulatory molecules.…”

“…145,201 Several studies using a range of Fe chelators have demonstrated their ability to induce apoptosis, 13 even though the exact signaling pathways that lead to this event upon Fe-depletion are not completely understood. For instance, DFO has been demonstrated to induce apoptosis in a number of cancer cell lines including ovarian cancer, 202 neuroblastoma, 203 Kaposi's sarcoma, 122 malignant oral keratinocytes 169 and cervical carcinomas. 204 Other chelators, including Triapine, 205 311, 90 Tachpyridine, 132,206,207 O-Trensox 208 and Dp44mT 93 have also been shown to induce apoptosis in a variety of neoplastic cell types both in vitro and in vivo.…”

“…209,210 A number of studies investigating the ability of Fe chelators to induce apoptosis examined their effects on various caspases. It has been demonstrated that incubation of cells with DFO increased the activity of caspase-3, -8 and -9, 169,202,211 while Dp44mT markedly increased the activity of caspase-3. 93 More importantly, numerous investigations have revealed that Fe chelators induce apoptosis through the mitochondrial pathway.…”