Pifithrin-α, an inhibitor of p53 transactivation, up-regulates COX-2 expression through an MAPK-dependent pathway.
Cyclooxygenase-2 (COX-2) has been reported to be elevated in many cancers, including breast and colorectal cancers, resulting in accumulation of prostaglandin E₂ in the cancer cell environment. In this study, we investigated the effect of pifithrin (PFT)-α, an inhibitor of p53 transactivation, on COX-2 expression in breast and fibrosarcoma cells. Our results showed that COX-2 expression was dose-dependently increased by PFT-α in MDA-MB231 breast cancer cells with mutant p53. In addition, the expression level of COX-2 was also increased by PFT-α in normal fibroblasts as well as in HT1080 fibrosarcoma cells with p53 wild-type cells. To verify the regulatory mechanism of COX-2 in response to PFT-α, we pretreated cells with a mitogen-activated protein kinase (MAPK) kinase (MEK)1/2 inhibitor (UO126) and a phosphoinositide-3 (PI-3K) inhibitor (LY294002). PFT-α-induced COX-2 expression was significantly decreased by UO126 and LY294002 in MDA-MB231 cells. However, the phosphorylation of extracellular signal-regulated kinase (ERK) was increased by PFT-α, but not Akt phosphorylation. Finally, we confirmed the correlation of the MEK and PI-3K pathway and COX-2 expression using the constitutively active (CA)-MEK and myr-Akt adenovirus systems. COX-2 expression was increased by CA-MEK transfection, but not by myr-Akt. Taken together, we have demonstrated that PFT-α-induced COX-2 expression is regulated through a MEK/ERK pathway in MDA-MB231 human breast cancer cells.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Sangmin
S
Kim
Jeonghun
J
Han
Se Kyung
SK
Lee
Sung Mo
SM
Hur
Minyoung
M
Koo
Dong Hui
DH
Cho
Soo Youn
SY
Bae
Min-Young
MY
Choi
Incheol
I
Shin
Jung-Hyun
JH
Yang
Seok Jin
SJ
Nam
Jeong Eon
JE
Lee
D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases