Modulation of ionizing radiation-induced G2 arrest by cyclooxygenase-2 and its inhibitor celecoxib.

Abstract

PURPOSE:

Prolongation or attenuation of ionizing radiation (IR)-induced G(2)-M arrest in cyclooxygenase-2 (COX-2) overexpressing or celecoxib-treated cells, respectively, has been previously observed. To better understand the molecular mechanisms involved, we investigated the molecules involved in G(2) checkpoint pathways after treatment with IR +/- celecoxib.

METHODS AND MATERIALS:

Various molecules in the G(2) checkpoint pathways were investigated in HCT-116-Mock and -COX-2 cells. Western blot, reverse transcriptase polymerase chain reaction, confocal microscopy, and fluorescence activated cell sorter (FACS) analyses were performed to investigate whether expression and activity of the ataxia telangiectasia and rad3-related (ATR) could be modulated by COX-2 and its selective inhibitors.

RESULTS:

COX-2 overexpression increased expression and activity of ATR after IR exposure. Celecoxib downregulated ATR in all tested cell lines independent of COX-2 expression, but downregulation was greater in COX-2 overexpressing cells after cells were irradiated. Celecoxib pretreatment before radiation caused strongly inhibited G(2) arrest.

CONCLUSIONS:

COX-2 appears to prolong IR-induced G(2) arrest by upregulating ATR. Celecoxib downregulated ATR preferentially in irradiated COX-2 overexpressing cells. Celecoxib may radiosensitize cancer cells by inhibiting G(2) arrest through ATR downregulation.

• Authors: Hyun Jung Jun, Young Mee Kim, Soo Yeon Park, Ji Sun Park, Eun Jung Lee, Shin Ae Choi, Hongryull Pyo
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 75 Issue 1 Pg. 225-34 (Sep 01 2009) ISSN: 1879-355X [Electronic] United States
• PMID: 19695440 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Cyclooxygenase 2 Inhibitors
• Pyrazoles
• RNA, Messenger
• Sulfonamides
• Cyclooxygenase 2
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• Celecoxib

Topics

• Ataxia Telangiectasia Mutated Proteins
• Celecoxib
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line
• Cyclooxygenase 2 (metabolism, physiology)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• DNA Repair (drug effects)
• Down-Regulation
• Flow Cytometry (methods)
• G2 Phase (drug effects, physiology, radiation effects)
• HCT116 Cells
• Humans
• Mitosis (radiation effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Pyrazoles (pharmacology)
• RNA, Messenger (metabolism)
• Radiation Tolerance (drug effects, physiology)
• Sulfonamides (pharmacology)
• Time Factors
• Up-Regulation