Mechanism of apoptotic induction by targeting of GST P and its targeting therapy

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Treatment of cells with a synthetic conjugate of DXR with GSH via glutaraldehyde (GSH-DXR) caused cytochrome c release from the mitochondria to the cytosol following potent activation of caspase-3 and -9 by typical DNA fragmentation. This apoptosis was regulated by the JNK-signaling pathway. In the present experiment, treatment of cells with GSH-DXR caused deamidation of Bcl-xL, which is localized in mitochondrial membrane. The deamidation of Bcl-xL was disappeared anti-apoptotic function and facilitated the release of cytochrome c from mitochondria. Moreover, GSH-DXR-induced JNK activation caused Bax translocation from cytosol to mitochondria, and also facilitated the release of cytochrome c. Bax was localized as 50-60 kDa Bax-complex with cytosolic protein in cytosol, and dissociated 25 kDa Bax was translocated to mitochondria by GSH-DXR-induced JNK activation. Overexpression of GST-P was suppressed JNK activation and decreased in both Bcl-xL deamidation and Bax translocation. These result were suggested that Bcl-2 family such as Bcl-xL and Bax, acted the induction of apoptosis as target molecule of JNK.When dimethylnitrosamine was injected intraperitoneally to rat, the formation of mini-foci in the liver was observed at two to three weeks after injection. Moreover, foci/nodule was increased at five to six weeks and nodule was formed thereafter. GST-P levels in Foci/nodule was increased extremely at five weeks and decreased gradually thereafter. However, no change in the level of JNK expression in each stage. It was suggested that suppression of JNK activity by GST-P increase in accordance with the formation of Foci/nodule caused to accelerate malignant alteration.