Abstract for presentation at 13th International Congress on Oral Pathology and Medicine

The p38 MAP Kinase Mediates Iron chelator-Induced Apoptosis and Differentiation of Immortalized and Malignant Human Oral Keratinocytes

  • Sun-Kyung Lee, Department of Oral & Maxillofacial Pathology, College of Dentistry, Wonkwang University, South Korea
  • Hyun-Ju Jang, Department of Oral & Maxillofacial Pathology, College of Dentistry, Wonkwang University, South Korea
  • Hwa-Jeong Lee, Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang University, South Korea
  • Eun-Cheol Kim, Department of Oral & Maxillofacial Pathology, College of Dentistry, Wonkwang University, South Korea

    • To determine the mechanism of cell death induced by iron chelators, we explored the pathways of the three structurally related mitogen-activated protein (MAP) kinase subfamilies during iron chelator-induced apoptosis and differentiation of oral precancerous and cancer cells. The iron chelator deferoxamine (DFO) exerted potent time- and dose-dependent inhibitory effects on the growth of IHOK and HN4 cells. The major mechanism of growth inhibition following DFO treatment was found to be apoptosis induction, as assessed by annexin V-FITC staining, cell cycle analysis, DNA laddering, and Hoechst staining. We report that DFO strongly activates the p38 MAP kinase and extracellular signal- regulated kinase (ERK), but does not activate the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). Of the three MAP kinase blockers used, the selective p38 MAP kinase inhibitor SB203580 and ERK inhibitor PD98059 protected oral premalignant and malignant cells against iron chelator-induced cell death, which indicates that the p38 MAP kinase serves as a major mediator of apoptosis induced by this iron chelator. DFO also evoked the release of cytochrome c from mitochondria, and induced the activation of caspase-3 and caspase-8 in oral cancer cells, which suggests that apoptosis occurs via the mitochondrion-mediated pathway. DFO enhanced the expression of Bax in IHOK and HN4 cells, consistent with their p53 status. Moreover, DFO downregulated the expression of Bcl-2 in oral cancer cells, which suggests that DFO- induced apoptosis of oral cancer and precancerous cells may be mediated by an increase in the ratio of pro-apoptotic to anti- apoptotic proteins. Interestingly, treatment of IHOK and HN4 cells with SB203580 abolished cytochrome c release, as well as the activation of caspase-3 and caspase-8. DFO suppressed the expression of epithelial differentiation markers, such as involucrin, transglutaminase II, CK6, and CK19, and this suppression was blocked by p38 and ERK MAP kinase inhibitors. The oral premalignant (IHOK) and malignant cells (HN4) showed differential responses to DFO with respect to the expression of cell cycle regulatory proteins, cell growth, and apoptosis. Collectively, the current study reveals that p38 MAP kinase plays an important role in iron chelator-mediated cell death and in the suppression of differentiation of oral premalignant and malignant cells, by activating a downstream apoptotic cascade that executes the cell death pathway.

    Conference Organiser - ICMS Pty Ltd