Proteasome Inhibitors Induce Apoptosis in Human Lung Cancer Cells Through a Positive Feedback Mechanism and the Subsequent Mcl-1 Protein Cleavage

Details

• Personal Author:
  Chapman J ; Reynolds SH ; Yuan BZ
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Chemistry Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Apoptosis Author Keywords: Proteasome Inhibitor 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 Mcl-1 Non-small Cell Lung Carcinoma Positive Feedback Mechanism Protein Cleavage Respiratory-system-disorders

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• ISSN:
  0950-9232
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  28
• Issue:
  43
• NIOSHTIC Number:
  nn:20036064
• Citation:
  Oncogene 2009 Oct; 28(43):3775-3786
• Contact Point Address:
  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
• Email:
  bby1@cdc.gov
• Federal Fiscal Year:
  2010
• Peer Reviewed:
  True
• Source Full Name:
  Oncogene
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:a1da5245b3e0fa8c896b78c13d1ea7303911607e781c3eafd9daaf8a7d7d45f4ab0ac08e646044b1ba43d17b39b114c3f90858e03f99244024f1f1d83a085b18
• Download URL:
  https://stacks.cdc.gov/view/cdc/187659/cdc_187659_DS1.pdf
• File Type:
  [PDF - 1.33 MB ]