Gene expressions in Jurkat cells poisoned by a sulphur mustard vesicant and the induction of apoptosis

Abstract

1 The sulphur mustard vesicant 2-chloroethylethyl sulphide (CEES) induced apoptosis in Jurkat cells. 2 Akt (PKB), a pivotal protein kinase which can block apoptosis and promotes cell survival, was identi®ed to be chie¯y down-regulated in a dose-dependent manner following CEES treatment. Functional analysis showed that the attendant Akt activity was simultaneously reduced. 3 PDK1, an upstream eector of Akt, was also down-regulated following CEES exposure, but two other upstream eectors of Akt, PI3-K and PDK2, remained unchanged. 4 The phosphorylation of Akt at Ser 473 and Thr 308 was signi®cantly decreased following CEES treatment, re¯ecting the suppressed kinase activity of both PDK1 and PDK2. 5 Concurrently, the anti-apoptotic genes, Bcl family, were down-regulated, in sharp contrast to the striking up-regulation of some death executioner genes, caspase 3, 6, and 8. 6 Based on these ®ndings, a model of CEES-induced apoptosis was established. These results suggest that CEES attacked the Akt pathway, directly or indirectly, by inhibiting Akt transcription, translation, and post-translation modi®cation. 7 Taken together, upon exposure to CEES, apoptosis was induced in Jurkat cells via the downregulation of the survival factors that normally prevent the activation of the death executioner genes, the caspases.

Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

“…Exposure of Jurkat T cells to CEES was recently shown to induce apoptotic death (Zhang et al, 2002). In the present study, calcein-AM staining revealed that incubation of normal lymphocytes and Jurkat cells for 24 h with 600 mM CEES resulted in an approximately 60 and 80% loss of viability, respectively ( Figure 1a).…”

“…Like SM, CEES induces vesiculation, as well as alkylates a wide range of biological molecules. Both SM and CEES alkylate DNA strands in the 7-position of guanine, the 3-position of adenine, and the O6-position of the guanine (Ludlum et al, 1986;Zhang et al, 2002). CEES is also involved in the induction of cell death by enhancement of the DNA repair process, which activates poly (ADP-ribose) polymerase (PARP) with the subsequent NAD depletion (Papirmeister et al, 1985) and oxidative stress (Husain et al, 1996).…”

“…Exposure of the Jurkat human T-cell line to CEES has recently been shown to induce biochemical and morphological changes characteristic of apoptotic cell death. These changes include chromatin condensation, degradation of genomic DNA into both high molecular weight and oligonucleosomal fragments, upregulation of caspase-3, -4, -6, -8, and -9, as well as downregulation of Akt (protein kinase B), the latter of which inhibits apoptotic signalling (Zhang et al, 2002).…”

Microarray Analysis of Mouse Ear Tissue Exposed to Bis-(2-chloroethyl) Sulfide: Gene Expression Profiles Correlate with Treatment Efficacy and An Established Clinical Endpoint

“…at ASPET Journals on May 12, 2018 jpet.aspetjournals.org Platteborze, 2003), HepG2 cells transfected with various stress gene reporter constructs (Schlager and Hart, 2000), and Jurkat cells exposed to the mustardrelated compound chloroethyl ethyl sulfide (CEES) (Zhang et al, 2002). Our previous studies show that vanilloids reduce skin edema and cytokine mRNA expression after SM exposure in a mouse model (Sabourin et al, 2003(Sabourin et al, , 2004b.…”

“…In addition the transcription factor nuclear factor-B, which is involved in both inflammation and apoptosis, is activated after SM exposure in cultured cells (Atkins et al, 2000;Schlager and Hart, 2000). In other systems, nuclear factor-B has been shown to be activated by CEES in guinea pig lung (Chatterjee et al, 2003), and the Akt pathway is perturbed by CEES exposure in Jurkat cells (Zhang et al, 2002). It is not clear how CEES exposure relates to SM exposure, but it is clear that signaling pathways associated with inflammatory response are activated by SM exposure.…”