Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of bim

Jin-Ming Yang, Peter O'Neill, Wei Jin, Ramsey Foty, Daniel J. Medina, Zude Xu, Mehnaaz Lomas, Greg M. Arndt, Yi Tang, Marian Nakada, Li Yan, William N. Hait

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.

Original languageEnglish (US)
Pages (from-to)9719-9727
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number14
DOIs
StatePublished - Apr 7 2006

Fingerprint

CD147 Antigens
Anoikis
Cells
Breast Neoplasms
Small Interfering RNA
Neoplasms
Proteasome Inhibitors
Mitogen-Activated Protein Kinase Kinases
Inhibition (Psychology)
Fibronectins
Caspase 3
Immunoglobulins
Tumors
Glycoproteins
Proteins
Phosphotransferases
Chemical activation
DNA Fragmentation
Growth
RNA Interference

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yang, Jin-Ming ; O'Neill, Peter ; Jin, Wei ; Foty, Ramsey ; Medina, Daniel J. ; Xu, Zude ; Lomas, Mehnaaz ; Arndt, Greg M. ; Tang, Yi ; Nakada, Marian ; Yan, Li ; Hait, William N. / Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of bim. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 14. pp. 9719-9727.
@article{1a73c6e9b6994f37a2610d47a8e7eaf3,
title = "Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of bim",
abstract = "Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.",
author = "Jin-Ming Yang and Peter O'Neill and Wei Jin and Ramsey Foty and Medina, {Daniel J.} and Zude Xu and Mehnaaz Lomas and Arndt, {Greg M.} and Yi Tang and Marian Nakada and Li Yan and Hait, {William N.}",
year = "2006",
month = "4",
day = "7",
doi = "10.1074/jbc.M508421200",
language = "English (US)",
volume = "281",
pages = "9719--9727",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "14",

}

Yang, J-M, O'Neill, P, Jin, W, Foty, R, Medina, DJ, Xu, Z, Lomas, M, Arndt, GM, Tang, Y, Nakada, M, Yan, L & Hait, WN 2006, 'Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of bim', Journal of Biological Chemistry, vol. 281, no. 14, pp. 9719-9727. https://doi.org/10.1074/jbc.M508421200

Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of bim. / Yang, Jin-Ming; O'Neill, Peter; Jin, Wei; Foty, Ramsey; Medina, Daniel J.; Xu, Zude; Lomas, Mehnaaz; Arndt, Greg M.; Tang, Yi; Nakada, Marian; Yan, Li; Hait, William N.

In: Journal of Biological Chemistry, Vol. 281, No. 14, 07.04.2006, p. 9719-9727.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of bim

AU - Yang, Jin-Ming

AU - O'Neill, Peter

AU - Jin, Wei

AU - Foty, Ramsey

AU - Medina, Daniel J.

AU - Xu, Zude

AU - Lomas, Mehnaaz

AU - Arndt, Greg M.

AU - Tang, Yi

AU - Nakada, Marian

AU - Yan, Li

AU - Hait, William N.

PY - 2006/4/7

Y1 - 2006/4/7

N2 - Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.

AB - Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.

UR - http://www.scopus.com/inward/record.url?scp=33646933890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646933890&partnerID=8YFLogxK

U2 - 10.1074/jbc.M508421200

DO - 10.1074/jbc.M508421200

M3 - Article

VL - 281

SP - 9719

EP - 9727

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 14

ER -