Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

E. Laane, K. Pokrovskaja Tamm, E. Buentke, Keisuke Ito, P. Khahariza, J. Oscarsson, M. Corcoran, A. C. Björklund, K. Hultenby, J. Lundin, M. Heyman, S. Söderhäll, J. Mazur, A. Porwit, P. P. Pandolfi, B. Zhivotovsky, T. Panaretakis, D. Grandér

Research output: Contribution to journalArticle

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Abstract

Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. Recent studies, however, showed that an alternative mode of cell death, autophagy, is involved in the response to anticancer drugs. The specific role of autophagy and its relationship to apoptosis remains, nevertheless, controversial: it can either lead to cell survival or can function in cell death. We show that dexamethasone induced autophagy upstream of apoptosis in acute lymphoblastic leukemia cells. Inhibition of autophagy by siRNA-mediated repression of Beclin 1 expression inhibited apoptosis showing an important role of autophagy in dexamethasone-induced cell death. Dexamethasone treatment caused an upregulation of promyelocytic leukemia protein, PML, its complex formation with protein kinase B or Akt and a PML-dependent Akt dephosphorylation. Initiation of autophagy and the onset of apoptosis were both dependent on these events. PML knockout thymocytes were resistant to dexamethasone-induced death and upregulation of PML correlated with the ability of dexamethasone to kill primary leukemic cells. Our data reveal key mechanisms of dexamethasone-induced cell death that may inform the development of improved treatment protocols for lymphoid malignancies.

Original languageEnglish (US)
Pages (from-to)1018-1029
Number of pages12
JournalCell Death and Differentiation
Volume16
Issue number7
DOIs
StatePublished - 2009
Externally publishedYes

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Lymphoid Leukemia
Autophagy
Dexamethasone
Cell Death
Apoptosis
Up-Regulation
Proto-Oncogene Proteins c-akt
Thymocytes
Clinical Protocols
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pharmaceutical Preparations
Small Interfering RNA
Glucocorticoids
Neoplasms
Cell Survival
Therapeutics

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. / Laane, E.; Tamm, K. Pokrovskaja; Buentke, E.; Ito, Keisuke; Khahariza, P.; Oscarsson, J.; Corcoran, M.; Björklund, A. C.; Hultenby, K.; Lundin, J.; Heyman, M.; Söderhäll, S.; Mazur, J.; Porwit, A.; Pandolfi, P. P.; Zhivotovsky, B.; Panaretakis, T.; Grandér, D.

In: Cell Death and Differentiation, Vol. 16, No. 7, 2009, p. 1018-1029.

Research output: Contribution to journalArticle

Laane, E, Tamm, KP, Buentke, E, Ito, K, Khahariza, P, Oscarsson, J, Corcoran, M, Björklund, AC, Hultenby, K, Lundin, J, Heyman, M, Söderhäll, S, Mazur, J, Porwit, A, Pandolfi, PP, Zhivotovsky, B, Panaretakis, T & Grandér, D 2009, 'Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy', Cell Death and Differentiation, vol. 16, no. 7, pp. 1018-1029. https://doi.org/10.1038/cdd.2009.46
Laane, E. ; Tamm, K. Pokrovskaja ; Buentke, E. ; Ito, Keisuke ; Khahariza, P. ; Oscarsson, J. ; Corcoran, M. ; Björklund, A. C. ; Hultenby, K. ; Lundin, J. ; Heyman, M. ; Söderhäll, S. ; Mazur, J. ; Porwit, A. ; Pandolfi, P. P. ; Zhivotovsky, B. ; Panaretakis, T. ; Grandér, D. / Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. In: Cell Death and Differentiation. 2009 ; Vol. 16, No. 7. pp. 1018-1029.
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