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

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.

Immunogenic death of colon cancer cells treated with oxaliplatin

“…Recent data, however, suggest that, in spite of its morphological uniformity, apoptosis can follow biochemically distinct subroutines, some of which may result in immunogenic cell death (Blachere et al, 2005;Casares et al, 2005;Sancho et al, 2008;Laane et al, 2009). When murine tumor cells are treated with distinct apoptosis inducers and then injected subcutaneously, in the absence of an adjuvant, they mostly fail to elicit an immune response that would protect the animals against subsequent challenge with live tumor cells (Casares et al, 2005;Obeid et al, 2007b).…”

“…Although CRT is usually located in the lumen of the endoplasmic reticulum (ER), yet it translocates to the cell surface in response to anthracyclines. This involves a complex signal transduction pathway, including an ER stress response, the subapoptotic activation of caspase-8 and the exocytosis-dependent co-translocation of CRT, together with another ER protein, ERp57, to the outer surface of the plasma membrane (Laane et al, 2009). Surface CRT serves as an engulfment signal (Obeid et al, 2007a, b) and similarly targets apoptotic cells for interaction with DCs and subsequent cross-presentation of tumor antigens (Zeng et al, 2006).…”

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

“…[90][91][92] Second, autophagy appears to be responsible for the death of some cancer cells (especially when they lack essential apoptotic modulators like BAX and BAK or caspases) 93,94 that respond to a selected panel of chemotherapeutic agents in vitro. 95,96 Nonetheless, in most known cases, autophagy constitutes a cytoprotective response activated by dying cells in the attempt to cope with stress, and its inhibition accelerates, rather than prevents, cell death. 97 Several methods may be used to determine whether the autophagic pathway is activated above baseline levels in the context of the cellular demise.…”

Glucocorticoid Elevation of Dexamethasone-induced Gene 2 (Dig2/RTP801/REDD1) Protein Mediates Autophagy in Lymphocytes

“…Although apoptosis induction by glucocorticoids has been the singular focus of investigators interested in understanding glucocorticoid-induced cell death for the past 25 years, we and others have recently documented that dexamethasone also induces macroautophagy (hereafter referred to as autophagy) in lymphocyte cell lines and in primary acute lymphoblastic leukemia cells (24,25). Autophagy is a highly conserved response to metabolic stress in which cellular proteins and organelles are degraded for the maintenance of homeostasis (26,27).…”