Bortezomib induces G 2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1

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

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44 Scopus citations

Abstract

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 G 2-M arrest in CRC cells. Investigation of G 2-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 G 2-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 G 2-M arrest through ROS-inducible ATM phosphorylation and demonstrate that bortezomib is a potential candidate for further investigations in the treatment for CRC patients.

Original languageEnglish (US)
Pages (from-to)76-82
Number of pages7
JournalInternational Journal of Oncology
Volume41
Issue number1
DOIs
StatePublished - Jul 2012

Keywords

  • Ataxia telangiectasia mutated
  • Bortezomib
  • Colon cancer
  • G -M arrest
  • Reactive oxygen species

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