Role of XIAP in inhibiting cisplatin-induced caspase activation in non-small cell lung cancer cells: a small molecule Smac mimic sensitizes for chemotherapy-induced apoptosis by enhancing caspase-3 activation.
X-linked IAP (XIAP) suppresses apoptosis by binding to initiator caspase-9 and effector caspases-3 and -7. Smac/DIABLO that is released from mitochondria during apoptosis can relieve its inhibitory activity. Here we investigated the role of XIAP in the previously found obstruction of chemotherapy-induced caspase-9 activation in non-small cell lung cancer (NSCLC) ... cells. Endogenously expressed XIAP bound active forms of both caspase-9 and caspase-3. However, downregulation of XIAP using shRNA or disruption of XIAP/caspase-9 interaction using a small molecule Smac mimic were unable to significantly induce caspase-9 activity, indicating that despite a strong binding potential of XIAP to caspase-9 it is not a major determinant in blocking caspase-9 in NSCLC cells. Although unable to revert caspase-9 blockage, the Smac mimic was able to enhance cisplatin-induced apoptosis, which was accompanied by increased caspase-3 activity. Additionally, a more detailed analysis of caspase activation in response to cisplatin indicated a reverse order of activation, whereby caspase-3 cleaved caspase-9 yielding an inactive form. Our findings indicate that the use of small molecule Smac mimic, when combined with an apoptotic trigger, may have therapeutic potential for the treatment of NSCLC.
Mesh Terms:
Antineoplastic Agents, Apoptosis, Carcinoma, Non-Small-Cell Lung, Caspase 3, Caspase 9, Cell Line, Tumor, Cisplatin, Down-Regulation, Enzyme Activation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Mitochondrial Proteins, Models, Biological, RNA Interference, Signal Transduction, X-Linked Inhibitor of Apoptosis Protein
Antineoplastic Agents, Apoptosis, Carcinoma, Non-Small-Cell Lung, Caspase 3, Caspase 9, Cell Line, Tumor, Cisplatin, Down-Regulation, Enzyme Activation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Mitochondrial Proteins, Models, Biological, RNA Interference, Signal Transduction, X-Linked Inhibitor of Apoptosis Protein
Exp. Cell Res.
Date: Apr. 01, 2007
PubMed ID: 17291493
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