Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells

Naoki Kawai, Shingo Tsuji, Masahiko Tsujii, Toshifumi Ito, Masakazu Yasumaru, Yoshimi Kakiuchi, Arata Kimura, Masato Komori, Yutaka Sasaki, Norio Hayashi, Sunao Kawano, Raymond Dubois, Masatsugu Hori

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis-related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src- or v-H-ras-expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates.

Original languageEnglish (US)
Pages (from-to)331-339
Number of pages9
JournalGastroenterology
Volume122
Issue number2
StatePublished - 2002
Externally publishedYes

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Tumor Necrosis Factor-alpha
Cadherins
src-Family Kinases
Peroxides
Ulcerative Colitis
Epithelial Cells
Catenins
Intestinal Mucosa
Protein Kinases
Agar
Cell Movement
Colorectal Neoplasms
Colon
Phosphorylation
Cytokines
Oxygen
Inflammation
Cell Line
Proteins

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Kawai, N., Tsuji, S., Tsujii, M., Ito, T., Yasumaru, M., Kakiuchi, Y., ... Hori, M. (2002). Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells. Gastroenterology, 122(2), 331-339.

Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells. / Kawai, Naoki; Tsuji, Shingo; Tsujii, Masahiko; Ito, Toshifumi; Yasumaru, Masakazu; Kakiuchi, Yoshimi; Kimura, Arata; Komori, Masato; Sasaki, Yutaka; Hayashi, Norio; Kawano, Sunao; Dubois, Raymond; Hori, Masatsugu.

In: Gastroenterology, Vol. 122, No. 2, 2002, p. 331-339.

Research output: Contribution to journalArticle

Kawai, N, Tsuji, S, Tsujii, M, Ito, T, Yasumaru, M, Kakiuchi, Y, Kimura, A, Komori, M, Sasaki, Y, Hayashi, N, Kawano, S, Dubois, R & Hori, M 2002, 'Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells', Gastroenterology, vol. 122, no. 2, pp. 331-339.
Kawai N, Tsuji S, Tsujii M, Ito T, Yasumaru M, Kakiuchi Y et al. Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells. Gastroenterology. 2002;122(2):331-339.
Kawai, Naoki ; Tsuji, Shingo ; Tsujii, Masahiko ; Ito, Toshifumi ; Yasumaru, Masakazu ; Kakiuchi, Yoshimi ; Kimura, Arata ; Komori, Masato ; Sasaki, Yutaka ; Hayashi, Norio ; Kawano, Sunao ; Dubois, Raymond ; Hori, Masatsugu. / Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells. In: Gastroenterology. 2002 ; Vol. 122, No. 2. pp. 331-339.
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abstract = "Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis-related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src- or v-H-ras-expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates.",
author = "Naoki Kawai and Shingo Tsuji and Masahiko Tsujii and Toshifumi Ito and Masakazu Yasumaru and Yoshimi Kakiuchi and Arata Kimura and Masato Komori and Yutaka Sasaki and Norio Hayashi and Sunao Kawano and Raymond Dubois and Masatsugu Hori",
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AU - Kawai, Naoki

AU - Tsuji, Shingo

AU - Tsujii, Masahiko

AU - Ito, Toshifumi

AU - Yasumaru, Masakazu

AU - Kakiuchi, Yoshimi

AU - Kimura, Arata

AU - Komori, Masato

AU - Sasaki, Yutaka

AU - Hayashi, Norio

AU - Kawano, Sunao

AU - Dubois, Raymond

AU - Hori, Masatsugu

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N2 - Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis-related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src- or v-H-ras-expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates.

AB - Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis-related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src- or v-H-ras-expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates.

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