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Bortezomib induces G2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1.
MedLine Citation:
PMID:  22552540     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Colorectal cancer (CRC) is one of the most common cancers; however, the development of drugs to treat the condition has reached a plateau. Bortezomib (PS-341, Velcade®) is a proteasome inhibitor approved for the treatment of hematological malignancies, including multiple myeloma. A few trials of bortezomib, alone or in combination chemotherapy, for CRC patients have been reported; however, the results were largely inconclusive. This may be related to a lack of understanding of the drug's mechanism of action. Although bortezomib is reported to induce apoptosis and cell cycle arrest in various human cancer cells, the inhibitory mechanism involved is not clear. In this study, the effect of bortezomib as a treatment for human CRC was examined in vitro using three CRC cell lines. Bortezomib induced G2-M arrest in CRC cells. Investigation of G2-M phase-related cell cycle proteins involved in the response to bortezomib revealed that the ataxia telangiectasia mutated (ATM)-cell cycle checkpoint kinase 1 (CHK1) pathway, but not ATM and Rad3-related (ATR), was activated, resulting in the inactivation of cdc2. Bortezomib caused an increase in intracellular reactive oxygen species (ROS) and treatment with the ROS scavenger NAC inhibited phosphorylation of ATM leading to a decrease in the number of cells in G2-M phase. Thus, increased ROS levels after exposure to bortezomib resulted in ATM phosphorylation. In addition, knockdown of endogenous ATM by RNA interference resulted in decreased sensitivity to bortezomib. These results suggest that bortezomib induces G2-M arrest through ROS-inducible ATM phosphorylation and demonstrate that bortezomib is a potential candidate for further investigations in the treatment for CRC patients.
Authors:
Yong Sang Hong; Seung-Woo Hong; Seung-Mi Kim; Dong-Hoon Jin; Jae-Sik Shin; Dok Hyun Yoon; Kyu-Pyo Kim; Jae-Lyun Lee; Dae Seog Heo; Jung Shin Lee; Tae Won Kim
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-26
Journal Detail:
Title:  International journal of oncology     Volume:  -     ISSN:  1791-2423     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-5-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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