The Mcl-1L Protein Confers Resistance of Human Non-Small Cell Lung Carcinoma NL20TA Cells to Arsenic Trioxide-Induced Apoptosis

Details

• Personal Author:
  Feng R ; Jefferson AM ; Reynolds SH ; Yuan BZ
• Description:
  Arsenic is an occupational and environmental carcinogen. Arsenic is also used as a therapeutic reagent in treating some hematopoietic malignancies through the induction of tumor cell apoptosis. Two opposing paradigms of arsenic in cancer development and in apoptosis induction support a general view that an alteration in apoptosis develops during tumor formation and confers resistance of the transformed cells to apoptosis from different stimuli. To understand the apoptotic response of normal lung epithelial cells and lung cancer cells to arsenic, we characterized some apoptosis-related biochemical events in NL20, a non-tumorigenic human lung epithelial cell line, and NL20TA, a tumorigenic lung cancer cell line, treated with arsenic trioxide (ATO). It was found that NL20 cells exhibited a positive apoptotic response to 10microM ATO through activation of the mitochondria-caspase 3 pathway, as manifested by Bid protein cleavage, selective mitochondrial release of the Smac protein and cleavage of the caspase 3, caspase 9 and PARP proteins. However, NL20TA cells showed no induction of apoptosis and no corresponding biochemical reactions following ATO treatment. The apoptosis in NL20 cells was associated with increased cellular oxidative stress; antioxidant treatment with MnTBAP and NAC inhibited ATO-induced apoptosis and the accompanying protein cleavages. Further investigation showed that the resistance of NL20TA cells to ATO-induced apoptosis was conferred by elevated Mcl-1L expression coupled with the loss of Mcl-1s/deltaTM expression, resulting in the inhibition of Smac release and caspase cleavage. This study provides a new insight into the mechanism of ATO-induced apoptosis and forms a basis for developing a novel therapeutic approach for treating lung cancers using a combination of anti-Mcl-1 and ATO treatments. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Cancer Cell-cultures Cell-function Cellular-function Cellular-reactions Lung-cancer Pulmonary-system-disorders Respiratory-system-disorders Therapeutic-agents
• ISSN:
  0197-016X
• Publisher:
  American Association for Cancer Research
• Document Type:
  Text
• Genre:
  Abstract or Summary ; Proceedings
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; Pennsylvania ; 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:
  48
• NIOSHTIC Number:
  nn:20032943
• Citation:
  Proceedings of the 98th American Association for Cancer Research Annual Meeting, April 14-18, 2007, Los Angeles, California. Philadelphia, PA: American Association for Cancer Research, 2007 Apr; 48:1146
• CAS Registry Number:
  Arsenic (CAS RN 7440-38-2) ; Arsenic trioxide (CAS RN 1327-53-3)
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  Proceedings of the 98th American Association for Cancer Research Annual Meeting, April 14-18, 2007, Los Angeles, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:00f6cdf6fd887d487f5cb310c8b668fedf8041c86dc79b884052d8801c4b991a2b8de802abbb3c1d5fceab1eb28dd857995af0822e9c8e83a8cf2089fb27628a
• Download URL:
  https://stacks.cdc.gov/view/cdc/186721/cdc_186721_DS1.pdf
• File Type:
  [PDF - 491.35 KB ]