Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2

Koga Komatsu, F. Gregory Buchanan, Sharada Katkuri, Jason D. Morrow, Hiroyasu Inoue, Michiro Otaka, Sumio Watanabe, Raymond N. DuBois

Research output: Contribution to journalArticle

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Abstract

Background & Aims: The mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK) pathway plays an important role in the regulation of cell growth and differentiation. Constitutively active components of the MEK signaling cascade can induce oncogenic transformation in many cell systems. Downstream MEK signaling also plays an important role in the regulation of cyclooxygenase-2 (COX-2), which is known to be involved in colorectal cancer. Therefore, we determined the role of COX-2 on the oncogenic potential of MEK1 in nontransformed rat intestinal epithelial cells. Methods: Constitutively active MEK1 (CA-MEK) mutant transfected rat intestinal epithelial cells were established and tested for their ability to grow in soft agar and form tumors in vivo. The effect of CA-MEK on sodium butyrate (NaB)-induced apoptosis was evaluated by the Annexin V assay. The transcriptional activity and posttranscriptional stability of the COX-2 gene was determined by transient transfection with COX-2 reporter variants and by Northern analysis. To address the role of COX-2 in tumor growth in vivo, xenografted mice were treated with celecoxib (100 mg/kg) or vehicle. Results: CA-MEK transfected RIE-1 and IEC-6 cells formed colonies in soft agar and tumors in nude mice. These cells showed resistance to NaB-induced apoptosis and cell cycle arrest. MEK activation led to increased expression of COX-2, Bcl-XL, Mcl-1, and phosphorylated Bad and decreased expression of Bak. Along with elevated COX-2 levels, PGI 2 and PGE2 levels were also increased. Pharmacologic inhibition of COX-2 inhibited MEK-induced tumor growth in vivo through enhanced apoptosis. Conclusions: COX-2 and its bioactive lipid products may play an important role in MEK-induced transformation.

Original languageEnglish (US)
Pages (from-to)577-590
Number of pages14
JournalGastroenterology
Volume129
Issue number2
DOIs
StatePublished - Aug 2005
Externally publishedYes

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Cyclooxygenase 2
Epithelial Cells
Mitogen-Activated Protein Kinase Kinases
Celecoxib
Apoptosis
Agar
Neoplasms
Growth
MAP Kinase Kinase Kinases
Butyric Acid
Annexin A5
Extracellular Signal-Regulated MAP Kinases
Cell Cycle Checkpoints
Mitogen-Activated Protein Kinases
Dinoprostone
Nude Mice
Protein Kinases
Transfection
Cell Differentiation
Colorectal Neoplasms

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Komatsu, K., Buchanan, F. G., Katkuri, S., Morrow, J. D., Inoue, H., Otaka, M., ... DuBois, R. N. (2005). Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2. Gastroenterology, 129(2), 577-590. https://doi.org/10.1016/j.gastro.2005.06.003

Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2. / Komatsu, Koga; Buchanan, F. Gregory; Katkuri, Sharada; Morrow, Jason D.; Inoue, Hiroyasu; Otaka, Michiro; Watanabe, Sumio; DuBois, Raymond N.

In: Gastroenterology, Vol. 129, No. 2, 08.2005, p. 577-590.

Research output: Contribution to journalArticle

Komatsu, K, Buchanan, FG, Katkuri, S, Morrow, JD, Inoue, H, Otaka, M, Watanabe, S & DuBois, RN 2005, 'Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2', Gastroenterology, vol. 129, no. 2, pp. 577-590. https://doi.org/10.1016/j.gastro.2005.06.003
Komatsu, Koga ; Buchanan, F. Gregory ; Katkuri, Sharada ; Morrow, Jason D. ; Inoue, Hiroyasu ; Otaka, Michiro ; Watanabe, Sumio ; DuBois, Raymond N. / Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2. In: Gastroenterology. 2005 ; Vol. 129, No. 2. pp. 577-590.
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abstract = "Background & Aims: The mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK) pathway plays an important role in the regulation of cell growth and differentiation. Constitutively active components of the MEK signaling cascade can induce oncogenic transformation in many cell systems. Downstream MEK signaling also plays an important role in the regulation of cyclooxygenase-2 (COX-2), which is known to be involved in colorectal cancer. Therefore, we determined the role of COX-2 on the oncogenic potential of MEK1 in nontransformed rat intestinal epithelial cells. Methods: Constitutively active MEK1 (CA-MEK) mutant transfected rat intestinal epithelial cells were established and tested for their ability to grow in soft agar and form tumors in vivo. The effect of CA-MEK on sodium butyrate (NaB)-induced apoptosis was evaluated by the Annexin V assay. The transcriptional activity and posttranscriptional stability of the COX-2 gene was determined by transient transfection with COX-2 reporter variants and by Northern analysis. To address the role of COX-2 in tumor growth in vivo, xenografted mice were treated with celecoxib (100 mg/kg) or vehicle. Results: CA-MEK transfected RIE-1 and IEC-6 cells formed colonies in soft agar and tumors in nude mice. These cells showed resistance to NaB-induced apoptosis and cell cycle arrest. MEK activation led to increased expression of COX-2, Bcl-XL, Mcl-1, and phosphorylated Bad and decreased expression of Bak. Along with elevated COX-2 levels, PGI 2 and PGE2 levels were also increased. Pharmacologic inhibition of COX-2 inhibited MEK-induced tumor growth in vivo through enhanced apoptosis. Conclusions: COX-2 and its bioactive lipid products may play an important role in MEK-induced transformation.",
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AU - Komatsu, Koga

AU - Buchanan, F. Gregory

AU - Katkuri, Sharada

AU - Morrow, Jason D.

AU - Inoue, Hiroyasu

AU - Otaka, Michiro

AU - Watanabe, Sumio

AU - DuBois, Raymond N.

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N2 - Background & Aims: The mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK) pathway plays an important role in the regulation of cell growth and differentiation. Constitutively active components of the MEK signaling cascade can induce oncogenic transformation in many cell systems. Downstream MEK signaling also plays an important role in the regulation of cyclooxygenase-2 (COX-2), which is known to be involved in colorectal cancer. Therefore, we determined the role of COX-2 on the oncogenic potential of MEK1 in nontransformed rat intestinal epithelial cells. Methods: Constitutively active MEK1 (CA-MEK) mutant transfected rat intestinal epithelial cells were established and tested for their ability to grow in soft agar and form tumors in vivo. The effect of CA-MEK on sodium butyrate (NaB)-induced apoptosis was evaluated by the Annexin V assay. The transcriptional activity and posttranscriptional stability of the COX-2 gene was determined by transient transfection with COX-2 reporter variants and by Northern analysis. To address the role of COX-2 in tumor growth in vivo, xenografted mice were treated with celecoxib (100 mg/kg) or vehicle. Results: CA-MEK transfected RIE-1 and IEC-6 cells formed colonies in soft agar and tumors in nude mice. These cells showed resistance to NaB-induced apoptosis and cell cycle arrest. MEK activation led to increased expression of COX-2, Bcl-XL, Mcl-1, and phosphorylated Bad and decreased expression of Bak. Along with elevated COX-2 levels, PGI 2 and PGE2 levels were also increased. Pharmacologic inhibition of COX-2 inhibited MEK-induced tumor growth in vivo through enhanced apoptosis. Conclusions: COX-2 and its bioactive lipid products may play an important role in MEK-induced transformation.

AB - Background & Aims: The mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK) pathway plays an important role in the regulation of cell growth and differentiation. Constitutively active components of the MEK signaling cascade can induce oncogenic transformation in many cell systems. Downstream MEK signaling also plays an important role in the regulation of cyclooxygenase-2 (COX-2), which is known to be involved in colorectal cancer. Therefore, we determined the role of COX-2 on the oncogenic potential of MEK1 in nontransformed rat intestinal epithelial cells. Methods: Constitutively active MEK1 (CA-MEK) mutant transfected rat intestinal epithelial cells were established and tested for their ability to grow in soft agar and form tumors in vivo. The effect of CA-MEK on sodium butyrate (NaB)-induced apoptosis was evaluated by the Annexin V assay. The transcriptional activity and posttranscriptional stability of the COX-2 gene was determined by transient transfection with COX-2 reporter variants and by Northern analysis. To address the role of COX-2 in tumor growth in vivo, xenografted mice were treated with celecoxib (100 mg/kg) or vehicle. Results: CA-MEK transfected RIE-1 and IEC-6 cells formed colonies in soft agar and tumors in nude mice. These cells showed resistance to NaB-induced apoptosis and cell cycle arrest. MEK activation led to increased expression of COX-2, Bcl-XL, Mcl-1, and phosphorylated Bad and decreased expression of Bak. Along with elevated COX-2 levels, PGI 2 and PGE2 levels were also increased. Pharmacologic inhibition of COX-2 inhibited MEK-induced tumor growth in vivo through enhanced apoptosis. Conclusions: COX-2 and its bioactive lipid products may play an important role in MEK-induced transformation.

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