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Proteasome inhibitors induce apoptosis in human lung cancer cells through a positive feedback mechanism and the subsequent Mcl-1 protein cleavage.

Authors
Yuan-BZ; Chapman-J; Reynolds-SH
Source
Oncogene 2009 Oct; 28(43):3775-3786
NIOSHTIC No.
20036064
Abstract
Proteasome inhibitors (PIs) are promising new therapeutic agents for treating non-small cell lung carcinoma (NSCLC). To investigate the mechanisms of action of PIs, we analyzed the proapoptotic activities of PIs (MG132 or Bortezomib) in NSCLC cells. We found that both MG132 (>1 mu M) and Bortezomib (>0.025 mu M) induced a significant apoptosis in NCI-H1703, a PI-sensitive NSCLC cell line, through initially activating the intrinsic apoptosis pathway, leading to the activation of a positive feedback mechanism (PFM), which then conveyed apoptosis signaling from the intrinsic pathway to the extrinsic pathway with formation of a signaling loop for maximal caspase activation. Mcl-1 and Noxa were identified to be the major anti-apoptotic and proapoptotic proteins, respectively, in PI-induced apoptosis and mutually exclusive in protein stability. Although the Mcl-1 protein was upregulated by proteasome inhibition, it was also subjected to caspase 3-dependent cleavage governed by the PFM. Moreover, it was revealed that Mcl-1 protein cleavage contributed to PFM-governed apoptosis in following inter-related ways: reducing the anti-apoptotic Mcl-1; generating the truncated proapoptotic Mcl-1(S); and inducing a shift of balance between Mcl-1 and Noxa. It was further manifested that tumor necrosis factor-related apoptosis-inducing ligand boosted MG132's proapoptotic activity through strengthening the PFM in both NCI-H1703 and NCI-H358, a PI-resistant NSCLC cell line. Therefore, this study provides a basis for enhancing the efficacy of PIs in treating NSCLC.
Keywords
Biological-effects; Cancer; Cell-alteration; Cell-biology; Cell-growth; Cell-metabolism; Cell-transformation; Cellular-reactions; Chemical-reactions; Chemotherapy; Lung-cancer; Lung-cells; Lung-disease; Lung-tissue; Respiratory-system-disorders; Author Keywords: proteasome inhibitor; non-small cell lung carcinoma; apoptosis; Mcl-1; positive feedback mechanism; protein cleavage
Contact
Dr B-Z Yuan, Laboratory of Molecular Genetics, Toxicology and Molecular Biology Branch, HELD, National Institute for Occupational Safety and Health, 1095 Willowdale Road, M/S: L-3014, Morgantown, WV 26505
CODEN
ONCNES
Publication Date
20091001
Document Type
Journal Article
Email Address
bby1@cdc.gov
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Issue of Publication
43
ISSN
0950-9232
NIOSH Division
HELD
Source Name
Oncogene
State
WV
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