Induction of TNF-α, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells

Masami Niiya, Kenji Niiya, Toru Kiguchi, Misako Shibakura, Noboru Asaumi, Katsuji Shinagawa, Fumihiko Ishimaru, Katsuyuki Kiura, Kazuma Ikeda, Hiroshi Ueoka, Mitsune Tanimoto

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Purpose: We have previously demonstrated doxorubicin-induced urokinase (uPA) and interleukin-8 (IL-8) expression in human H69 small-cell lung carcinoma (SCLC) cells by a microarray technique using Human Cancer Chip version 2, in which 425 human "cancer-related" genes are spotted on the plates. The microarray analysis also revealed a significant induction of tumor necrosis factor-alpha (TNF-α), and doxorubicin-induced macrophage chemoattractant protein-1 (MCP-1) expression was demonstrated by an RNase protection assay. We extended the study by testing the effects of doxorubicin on the induction of TNF-α, uPA, IL-8 and MCP-1 in other types of lung carcinoma cells. Methods: We investigated the effects of doxorubicin on the expression of TNF-α, uPA, IL-8 and MCP-1 in 12 human lung carcinoma cell lines, including five SCLC, three adenocarcinoma and four squamous cell carcinoma cells. The surface expression of their receptors was also investigated. Results: TNF-α was significantly induced in three cell lines, H69, SBC-7 (SCLC) and PC-9 (adenocarcinoma), uPA in five cell lines, H69, SBC-7, EBC-1 (squamous cell), EBC-2 (squamous cell), and Sq-1 (squamous cell), IL-8 in three cell lines, H69, PC-9 and EBC-1, and MCP-1 in five cell lines, H69, SBC-3 (SCLC), SBC-7, PC-9 and Sq-1. In H69 cells, TNF-α antigen levels were increased approximately fivefold in the conditioned medium of doxorubicin-treated cells, in parallel with an increase in mRNA levels. As with uPA and IL-8, the maximum induction was observed at the "sublethal" concentrations of 2 and 4 μM at which cell growth was slightly inhibited 24 h after treatment. Furthermore, the cells did not express receptors including types I and II TNF-α receptors, uPA receptor (uPAR), C-x-C-chemokine receptor-1 (CXCR-1), or C-C-chemokine receptor-2, corresponding to TNF-α, uPA, IL-8 and MCP-1, respectively, that were induced by doxorubicin in the cells, although SBC-7 cells expressed uPAR, and EBC-1 cells expressed CXCR-1. Conclusions: TNF-α, uPA, IL-8 and MCP-1 induced and secreted from tumor cells upon doxorubicin stimulation may activate surrounding cells expressing the receptors such as neutrophils and monocytes/macrophages in a paracrine fashion. TNF-α is a major proinflammatory cytokine, and IL-8 and MCP-1 are major chemoattractants for neutrophils and monocytes/macrophages, respectively. Furthermore, uPA activates matrix metalloproteinase 9 which can truncate and activate IL-8. Thus, the simultaneous induction of TNF-α, uPA, IL-8 and MCP-1 may enhance the interaction between tumor and inflammatory/immune cells, and augment cytotoxicity.

Original languageEnglish
Pages (from-to)391-398
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume52
Issue number5
DOIs
Publication statusPublished - Nov 2003

Fingerprint

Macrophages
Chemotactic Factors
Interleukin-8
Doxorubicin
Tumor Necrosis Factor-alpha
Cells
Carcinoma
Lung
Proteins
Small Cell Lung Carcinoma
CC Chemokines
Chemokine Receptors
C Chemokines
Cell Line
Epithelial Cells
Microarrays
Tumors
Monocytes
Adenocarcinoma
Neutrophils

Keywords

  • Doxorubicin
  • Gene expression
  • IL-8
  • Lung cancer
  • MCP-1
  • Tumor necrosis factor-α (TNF-α)
  • uPA

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Induction of TNF-α, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells. / Niiya, Masami; Niiya, Kenji; Kiguchi, Toru; Shibakura, Misako; Asaumi, Noboru; Shinagawa, Katsuji; Ishimaru, Fumihiko; Kiura, Katsuyuki; Ikeda, Kazuma; Ueoka, Hiroshi; Tanimoto, Mitsune.

In: Cancer Chemotherapy and Pharmacology, Vol. 52, No. 5, 11.2003, p. 391-398.

Research output: Contribution to journalArticle

Niiya, M, Niiya, K, Kiguchi, T, Shibakura, M, Asaumi, N, Shinagawa, K, Ishimaru, F, Kiura, K, Ikeda, K, Ueoka, H & Tanimoto, M 2003, 'Induction of TNF-α, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells', Cancer Chemotherapy and Pharmacology, vol. 52, no. 5, pp. 391-398. https://doi.org/10.1007/s00280-003-0665-1
Niiya, Masami ; Niiya, Kenji ; Kiguchi, Toru ; Shibakura, Misako ; Asaumi, Noboru ; Shinagawa, Katsuji ; Ishimaru, Fumihiko ; Kiura, Katsuyuki ; Ikeda, Kazuma ; Ueoka, Hiroshi ; Tanimoto, Mitsune. / Induction of TNF-α, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells. In: Cancer Chemotherapy and Pharmacology. 2003 ; Vol. 52, No. 5. pp. 391-398.
@article{6ba2fc89bd8b4480a662d48adcee889b,
title = "Induction of TNF-α, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells",
abstract = "Purpose: We have previously demonstrated doxorubicin-induced urokinase (uPA) and interleukin-8 (IL-8) expression in human H69 small-cell lung carcinoma (SCLC) cells by a microarray technique using Human Cancer Chip version 2, in which 425 human {"}cancer-related{"} genes are spotted on the plates. The microarray analysis also revealed a significant induction of tumor necrosis factor-alpha (TNF-α), and doxorubicin-induced macrophage chemoattractant protein-1 (MCP-1) expression was demonstrated by an RNase protection assay. We extended the study by testing the effects of doxorubicin on the induction of TNF-α, uPA, IL-8 and MCP-1 in other types of lung carcinoma cells. Methods: We investigated the effects of doxorubicin on the expression of TNF-α, uPA, IL-8 and MCP-1 in 12 human lung carcinoma cell lines, including five SCLC, three adenocarcinoma and four squamous cell carcinoma cells. The surface expression of their receptors was also investigated. Results: TNF-α was significantly induced in three cell lines, H69, SBC-7 (SCLC) and PC-9 (adenocarcinoma), uPA in five cell lines, H69, SBC-7, EBC-1 (squamous cell), EBC-2 (squamous cell), and Sq-1 (squamous cell), IL-8 in three cell lines, H69, PC-9 and EBC-1, and MCP-1 in five cell lines, H69, SBC-3 (SCLC), SBC-7, PC-9 and Sq-1. In H69 cells, TNF-α antigen levels were increased approximately fivefold in the conditioned medium of doxorubicin-treated cells, in parallel with an increase in mRNA levels. As with uPA and IL-8, the maximum induction was observed at the {"}sublethal{"} concentrations of 2 and 4 μM at which cell growth was slightly inhibited 24 h after treatment. Furthermore, the cells did not express receptors including types I and II TNF-α receptors, uPA receptor (uPAR), C-x-C-chemokine receptor-1 (CXCR-1), or C-C-chemokine receptor-2, corresponding to TNF-α, uPA, IL-8 and MCP-1, respectively, that were induced by doxorubicin in the cells, although SBC-7 cells expressed uPAR, and EBC-1 cells expressed CXCR-1. Conclusions: TNF-α, uPA, IL-8 and MCP-1 induced and secreted from tumor cells upon doxorubicin stimulation may activate surrounding cells expressing the receptors such as neutrophils and monocytes/macrophages in a paracrine fashion. TNF-α is a major proinflammatory cytokine, and IL-8 and MCP-1 are major chemoattractants for neutrophils and monocytes/macrophages, respectively. Furthermore, uPA activates matrix metalloproteinase 9 which can truncate and activate IL-8. Thus, the simultaneous induction of TNF-α, uPA, IL-8 and MCP-1 may enhance the interaction between tumor and inflammatory/immune cells, and augment cytotoxicity.",
keywords = "Doxorubicin, Gene expression, IL-8, Lung cancer, MCP-1, Tumor necrosis factor-α (TNF-α), uPA",
author = "Masami Niiya and Kenji Niiya and Toru Kiguchi and Misako Shibakura and Noboru Asaumi and Katsuji Shinagawa and Fumihiko Ishimaru and Katsuyuki Kiura and Kazuma Ikeda and Hiroshi Ueoka and Mitsune Tanimoto",
year = "2003",
month = "11",
doi = "10.1007/s00280-003-0665-1",
language = "English",
volume = "52",
pages = "391--398",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Induction of TNF-α, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells

AU - Niiya, Masami

AU - Niiya, Kenji

AU - Kiguchi, Toru

AU - Shibakura, Misako

AU - Asaumi, Noboru

AU - Shinagawa, Katsuji

AU - Ishimaru, Fumihiko

AU - Kiura, Katsuyuki

AU - Ikeda, Kazuma

AU - Ueoka, Hiroshi

AU - Tanimoto, Mitsune

PY - 2003/11

Y1 - 2003/11

N2 - Purpose: We have previously demonstrated doxorubicin-induced urokinase (uPA) and interleukin-8 (IL-8) expression in human H69 small-cell lung carcinoma (SCLC) cells by a microarray technique using Human Cancer Chip version 2, in which 425 human "cancer-related" genes are spotted on the plates. The microarray analysis also revealed a significant induction of tumor necrosis factor-alpha (TNF-α), and doxorubicin-induced macrophage chemoattractant protein-1 (MCP-1) expression was demonstrated by an RNase protection assay. We extended the study by testing the effects of doxorubicin on the induction of TNF-α, uPA, IL-8 and MCP-1 in other types of lung carcinoma cells. Methods: We investigated the effects of doxorubicin on the expression of TNF-α, uPA, IL-8 and MCP-1 in 12 human lung carcinoma cell lines, including five SCLC, three adenocarcinoma and four squamous cell carcinoma cells. The surface expression of their receptors was also investigated. Results: TNF-α was significantly induced in three cell lines, H69, SBC-7 (SCLC) and PC-9 (adenocarcinoma), uPA in five cell lines, H69, SBC-7, EBC-1 (squamous cell), EBC-2 (squamous cell), and Sq-1 (squamous cell), IL-8 in three cell lines, H69, PC-9 and EBC-1, and MCP-1 in five cell lines, H69, SBC-3 (SCLC), SBC-7, PC-9 and Sq-1. In H69 cells, TNF-α antigen levels were increased approximately fivefold in the conditioned medium of doxorubicin-treated cells, in parallel with an increase in mRNA levels. As with uPA and IL-8, the maximum induction was observed at the "sublethal" concentrations of 2 and 4 μM at which cell growth was slightly inhibited 24 h after treatment. Furthermore, the cells did not express receptors including types I and II TNF-α receptors, uPA receptor (uPAR), C-x-C-chemokine receptor-1 (CXCR-1), or C-C-chemokine receptor-2, corresponding to TNF-α, uPA, IL-8 and MCP-1, respectively, that were induced by doxorubicin in the cells, although SBC-7 cells expressed uPAR, and EBC-1 cells expressed CXCR-1. Conclusions: TNF-α, uPA, IL-8 and MCP-1 induced and secreted from tumor cells upon doxorubicin stimulation may activate surrounding cells expressing the receptors such as neutrophils and monocytes/macrophages in a paracrine fashion. TNF-α is a major proinflammatory cytokine, and IL-8 and MCP-1 are major chemoattractants for neutrophils and monocytes/macrophages, respectively. Furthermore, uPA activates matrix metalloproteinase 9 which can truncate and activate IL-8. Thus, the simultaneous induction of TNF-α, uPA, IL-8 and MCP-1 may enhance the interaction between tumor and inflammatory/immune cells, and augment cytotoxicity.

AB - Purpose: We have previously demonstrated doxorubicin-induced urokinase (uPA) and interleukin-8 (IL-8) expression in human H69 small-cell lung carcinoma (SCLC) cells by a microarray technique using Human Cancer Chip version 2, in which 425 human "cancer-related" genes are spotted on the plates. The microarray analysis also revealed a significant induction of tumor necrosis factor-alpha (TNF-α), and doxorubicin-induced macrophage chemoattractant protein-1 (MCP-1) expression was demonstrated by an RNase protection assay. We extended the study by testing the effects of doxorubicin on the induction of TNF-α, uPA, IL-8 and MCP-1 in other types of lung carcinoma cells. Methods: We investigated the effects of doxorubicin on the expression of TNF-α, uPA, IL-8 and MCP-1 in 12 human lung carcinoma cell lines, including five SCLC, three adenocarcinoma and four squamous cell carcinoma cells. The surface expression of their receptors was also investigated. Results: TNF-α was significantly induced in three cell lines, H69, SBC-7 (SCLC) and PC-9 (adenocarcinoma), uPA in five cell lines, H69, SBC-7, EBC-1 (squamous cell), EBC-2 (squamous cell), and Sq-1 (squamous cell), IL-8 in three cell lines, H69, PC-9 and EBC-1, and MCP-1 in five cell lines, H69, SBC-3 (SCLC), SBC-7, PC-9 and Sq-1. In H69 cells, TNF-α antigen levels were increased approximately fivefold in the conditioned medium of doxorubicin-treated cells, in parallel with an increase in mRNA levels. As with uPA and IL-8, the maximum induction was observed at the "sublethal" concentrations of 2 and 4 μM at which cell growth was slightly inhibited 24 h after treatment. Furthermore, the cells did not express receptors including types I and II TNF-α receptors, uPA receptor (uPAR), C-x-C-chemokine receptor-1 (CXCR-1), or C-C-chemokine receptor-2, corresponding to TNF-α, uPA, IL-8 and MCP-1, respectively, that were induced by doxorubicin in the cells, although SBC-7 cells expressed uPAR, and EBC-1 cells expressed CXCR-1. Conclusions: TNF-α, uPA, IL-8 and MCP-1 induced and secreted from tumor cells upon doxorubicin stimulation may activate surrounding cells expressing the receptors such as neutrophils and monocytes/macrophages in a paracrine fashion. TNF-α is a major proinflammatory cytokine, and IL-8 and MCP-1 are major chemoattractants for neutrophils and monocytes/macrophages, respectively. Furthermore, uPA activates matrix metalloproteinase 9 which can truncate and activate IL-8. Thus, the simultaneous induction of TNF-α, uPA, IL-8 and MCP-1 may enhance the interaction between tumor and inflammatory/immune cells, and augment cytotoxicity.

KW - Doxorubicin

KW - Gene expression

KW - IL-8

KW - Lung cancer

KW - MCP-1

KW - Tumor necrosis factor-α (TNF-α)

KW - uPA

UR - http://www.scopus.com/inward/record.url?scp=0242298096&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0242298096&partnerID=8YFLogxK

U2 - 10.1007/s00280-003-0665-1

DO - 10.1007/s00280-003-0665-1

M3 - Article

C2 - 12908082

AN - SCOPUS:0242298096

VL - 52

SP - 391

EP - 398

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 5

ER -