Presentation Title

Interactions between Apoptosis and Autophagy in Glucocorticoid –evoked death of human leukemic CEM cells.

Start Date

November 2016

End Date

November 2016

Location

HUB 302-73

Type of Presentation

Poster

Abstract

Glucocorticoids (GCs) bind to GC receptors and initiate a pathway for programmed cell death (PCD) in GC-sensitive human leukemic CEM cell lines. While GCs are widely thought to induce Type I PCD (apoptosis), recent studies suggest overlapping influences of Type II PCD (autophagy). The synthetic GC dexamethasone (Dex) kills CEMC7-14 cells by apoptosis while CEMC1-15 cells are resistant to Dex. Ectopic expression of mouse E4BP4 (CEMC1-5mE#3 cells) sensitizes CEMC1-15 cells to Dex-mediated responses. We hypothesized that Dex-mediated activation of autophagy blunted or inhibited apoptosis in CEM cells, and that inhibition of apoptosis could divert cells toward autophagic death. To test which cell death program Dex activated, all three lines of CEM cells were treated with Dex, NS3694 (the apoptosis inhibitor), and Cpd18 (the autophagy inhibitor), either alone or in combination for evaluation of cell viability. Result indicated that inhibiting autophagy by Cdp18 significantly promoted Dex-induced cell death in the sensitive cells (p<0.05), but did not improve responsiveness of resistant CEMC1-15 cells to Dex (p>0.05). In contrast, the apoptosis inhibitor NS3694 significantly increased cell viability /proliferation in all three cell lines (p<0.05). Flow cytometric analysis confirmed that the cell death represented type I PCD (apoptosis). We concluded that NS3694 is an effective anti-apoptotic agent. Inhibition of autophagy potentiated Dex-mediated apoptosis in the sensitive cells suggesting that autophagy and apoptosis represent mutually antagonistic responses within cells. However, since blocking autophagy did not restore Dex sensitivity in CEMC1-15 cells, resistance to both pathways may be coupled and mediated by a common intermediate(s).

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Interactions between Apoptosis and Autophagy in Glucocorticoid –evoked death of human leukemic CEM cells.

HUB 302-73

Glucocorticoids (GCs) bind to GC receptors and initiate a pathway for programmed cell death (PCD) in GC-sensitive human leukemic CEM cell lines. While GCs are widely thought to induce Type I PCD (apoptosis), recent studies suggest overlapping influences of Type II PCD (autophagy). The synthetic GC dexamethasone (Dex) kills CEMC7-14 cells by apoptosis while CEMC1-15 cells are resistant to Dex. Ectopic expression of mouse E4BP4 (CEMC1-5mE#3 cells) sensitizes CEMC1-15 cells to Dex-mediated responses. We hypothesized that Dex-mediated activation of autophagy blunted or inhibited apoptosis in CEM cells, and that inhibition of apoptosis could divert cells toward autophagic death. To test which cell death program Dex activated, all three lines of CEM cells were treated with Dex, NS3694 (the apoptosis inhibitor), and Cpd18 (the autophagy inhibitor), either alone or in combination for evaluation of cell viability. Result indicated that inhibiting autophagy by Cdp18 significantly promoted Dex-induced cell death in the sensitive cells (p<0.05), but did not improve responsiveness of resistant CEMC1-15 cells to Dex (p>0.05). In contrast, the apoptosis inhibitor NS3694 significantly increased cell viability /proliferation in all three cell lines (p<0.05). Flow cytometric analysis confirmed that the cell death represented type I PCD (apoptosis). We concluded that NS3694 is an effective anti-apoptotic agent. Inhibition of autophagy potentiated Dex-mediated apoptosis in the sensitive cells suggesting that autophagy and apoptosis represent mutually antagonistic responses within cells. However, since blocking autophagy did not restore Dex sensitivity in CEMC1-15 cells, resistance to both pathways may be coupled and mediated by a common intermediate(s).