Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

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

“…We reported earlier that activated Bax was detected in Dex-induced apoptotic cells with fragmented nuclei. 17 Indeed, cells with MDCpositive autophagosomes were not Bax-positive, again indicating that the features of apoptosis are later events in Dex-induced cell death (Figure 3b). Finally, triple staining for MDC/Annexin V/TMRE of Dex-treated cells indicated that the MDC-high cell population consisted of TMRE-positive/Annexin V-negative cells (Figure 3c), providing additional evidence that autophagy precedes the manifestation of apoptosis.…”

“…We have earlier shown that Dexinduced cell death in ALL cell lines and primary lymphoblasts of ALL patients is mediated through the mitochondrial apoptotic pathway associated with the activation of Bak and Bax, downregulation of Bcl-2 and Bcl-xL, loss of mitochondrial membrane potential (DCm), caspase activation, loss of propidium iodide (PI) exclusion and exposure of phosphatidylserine on the plasma membrane. 17 Figure 1A represents a typical analysis of apoptosis induced by Dex in ALL cell lines: two -sensitive, RS4;11 and SUP-B15, and one -resistant, Reh cells. As the upstream signaling leading to apoptosis induced by Dex is largely unknown, we investigated the morphological characteristics of Dex-induced cell death using electron microscopy.…”

“…We showed before that Dex-induced apoptosis is mediated through the activation of Bak, an event that correlated well with other apoptotic markers such as loss of mitochondrial membrane potential and re-distribution of plasma membrane phosphatidyl serines (Annexin Vpositivity). 17 Therefore, we used stainings for active Bak to assess cell death and analyzed the amounts of Bak-positive cells in the gated GFP-positive population. Akt-DD significantly protected from Dex-induced Bak activation (Figure 5d).…”

“…An earlier study by our group has shown that Dex-treatment causes downregulation of the antiapoptotic Bcl-2 family members Bcl-2 and Bcl-XL at the mRNA level. 17 Bcl-2 and Bcl-XL have been found to interact with Beclin 1, and downregulation of Bcl-2 was also found to trigger autophagy. 34 Thus, the effect of Dex on Bcl-2 and Bcl-XL might presumably contribute to the induction of autophagy in human ALL cells.…”

“…Furthermore, Dex treatment in the presence of lysosomal inhibitors led to an increased LC3-II conversion indicating that Dex enhanced formation of autophagosomes rather than decreased the rate of degradation of these transient vesicles. As we and others have shown that Dex induces a mitochondria-dependent apoptosis, 17 c). Statistical analysis was carried out using Pearsons correlation r ¼ 0.85 (P-value significant at 0.01 level).…”