PARENT SESSION
1:30 PM to 3:30 PM
Wednesday, April 24, 2002
Poster Session 26 Apoptosis
Room: Nevada Exhibition Center

(P31-304) Low glucose enhances TRAIL-induced reduction of Akt expression: Involvement of caspase-3.

Kim, Jin^*,1, Lee, Yong¹, ¹ Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA

ABSTRACT-
We previously observed that glucose deprivation enhances TRAIL-induced apoptotic death as well as caspase activation (caspase-3, -9, and -8) in human prostate adenocarcinoma DU-145 cells (Oncogene, In press). In this study, we employed caspase-3-deficient MCF-7 breast cancer cells to examine a possible role of caspase-3 in glucose deprivation-enhanced TRAIL cytotoxicity. Combined glucose deprivation and 200 ng/ml TRAIL treatment markedly induced cytotoxicity in caspase-3 cDNA transfected cells (MCF-7/Casp-3) but not in control vector transfected cells (MCF-7/Vector). We also observed that the level of Akt, an antiapoptotic protein, was reduced by treatment with TRAIL in MCF-7/Casp-3 cells but not in MCF-7/Vector cells. The reduction of Akt expression by TRAIL was promoted in the absence of glucose in MCF-7/Casp-3 cells. However, pretreatment with 20 uM Z-LEHD-FMK, a caspase-9 inhibitor, protected MCF-7/Casp-3 cells from the combinatorial treatment of TRAIL and glucose deprivation-induced cytotoxicity. This compound also prevented the reduction of Akt level during the combinatorial treatment. Moreover, this Akt reduction was not inhibited by treatment with MG-132, a proteosome inhibitor. Thus, our results suggest that caspase-3 is involved in the reduction of Akt level and the involvement of caspase-3 is mediated through caspase-9 activation. The reduction of Akt level is also due to cleavage of Akt rather than degradation of Akt.

KEYWORDS: glucose deprivation, TRAIL, Akt, caspase-3