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Differential regulation of extrinsic and intrinsic cell death pathways by protein kinase C.. Alakananda Basu; Ayako Miura (2002) International journal of molecular medicine display abstract
The pathway of cell death depends on the apoptotic stimuli as well as on the cell type. In the present study, we have compared how extrinsic and intrinsic cell death pathways are regulated by the protein kinase C (PKC) signal transduction pathway in the same cell type. PDBu, an activator of PKC, potentiated cell death mediated by the DNA damaging agent cisplatin but it blocked tumor necrosis factor-alpha (TNF)-induced cell death in HeLa cells. Conversely, rottlerin, an inhibitor of PKCdelta, decreased sensitivity of HeLa cells to cisplatin but it potentiated TNF-induced cell death. Although both TNF and cisplatin caused activation of caspases, PKC modulators had opposing effects on caspase activation. Rottlerin inhibited mitochondrial or intrinsic cell death pathway by inhibiting cisplatin-induced processing of apical caspase-9 and its downstream caspases. In contrast, it potentiated receptor-initiated or extrinsic cell death pathway by enhancing activation of caspase-2 and/or caspase-8. These results suggest that PKC acts at distinct steps to regulate receptor-mediated and DNA damage-induced apoptosis.
Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP.. Eun Hee Kim; Seung U Kim; Kyeong Sook Choi (2005) Oncogene display abstract
In the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, treatment with TRAIL in combination with subtoxic doses of rottlerin induced rapid apoptosis. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in these cells, treatment with rottlerin efficiently recovered TRAIL-induced activation of caspases. Treatment with rottlerin significantly decreased Cdc2 activity through the downregulation of cyclin A, cyclin B, and Cdc2 proteins, whereas the sensitizing effect of rottlerin on TRAIL-induced apoptosis was independent of PKCdelta activity. Furthermore, treatment with rottlerin downregulated the protein levels of survivin and X-chromosome-linked IAP (XIAP), two major caspase inhibitors. Forced expression of Cdc2 together with cyclin B attenuated rottlerin-potentiated TRAIL-induced apoptosis by over-riding the rottlerin-mediated downregulation of survivin and XIAP protein levels. Taken together, inhibition of Cdc2 activity and the subsequent downregulation of survivin and XIAP by subtoxic doses of rottlerin contribute to amplification of caspase cascades, thereby overcoming resistance of glioma cells to TRAIL-mediated apoptosis. Since rottlerin can sensitize Bcl-2- or Bcl-xL-overexpressing glioma cells but not human astrocytes to TRAIL-induced apoptosis, this combined treatment may offer an attractive strategy for safely treating resistant gliomas.
The PKC delta inhibitor, rottlerin, induces apoptosis of haematopoietic cell lines through mitochondrial membrane depolarization and caspases' cascade.. Ya-Fan Liao; Ying-Cheng Hung; Wen-Huei Chang; Gregory J Tsay; Tzyh-Chyuan Hour; Hui-Chih Hung; Guang-Yaw Liu (2005) Life sciences display abstract
Rottlerin is a widely selective protein kinase C delta (PKCdelta) inhibitor isolated from Mallotus philippinensis. It shown to be effective against several human tumor cell lines and in potentiating chemotherapy-induced cytotoxcicity. Using the trypan blue exclusion assay, we demonstrated that rottlerin reduced the viability in a dose- and time-dependent manner of human leukemia HL60 cells, human acute T cell leukemia Jurkat cells and mouse macrophage RAW 264.7 cells. Rottlerin caused apoptosis and the apaptotic processing was inhibited by a caspase inhibitor, z-VAD-fmk, in these haematopoietic cells. The apoptosis-inducing activities were determined by nuclear condensation, sub-G1 appearance, DNA fragmentation, loss of mitochondrial membrane potential (Deltapsim), release of mitochondrial cytochrome c into cytoplasm and proteolytic activation of caspase 9 and 3. Expression of PKCdelta and Bcl-2 protein inhibited Deltapsim change and repressed cell death. These studies suggest that the cytotoxic effects of rottlerin through inhibition of PKCdelta cause mitochondrial dysfunction, cytochrome c release from mitochondria into cytoplasm and the activation of caspases' cascade.