The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism

Ju Lee Eun, Ha Whang Jin, Kyeong Jeon Nam, Jin Kim

Research output: Chapter in Book/Report/Conference proceedingConference contribution

27 Citations (Scopus)

Abstract

Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to characterize the effects of ZD1839 with regard to human OSCC cell growth and invasion/migration. The YD-10B cells represent a highly invasive human OSCC cell line, which has a frame shift p53 mutation. ZD1839 inhibited the growth of the cell line in a time- and dose-dependent manner. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest. This induction of a G1 cell cycle arrest was associated with the upregulation of cyclin-dependent kinase inhibitors (CDKI) p27KIP1 and p21CIP1/WAF1. The upregulation of CDKI in ZD1839 treated cell lines may be mediated by a p53-independent and hnRNPC1/C2-dependent pathway. In addition, 100 nM ZD1839 demonstrated that both MMP-2 and MMP-9 enzyme activity were decreased by ∼25-30%. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that ZD1839 downregulated the uPAR mRNA level. These results might be associated with the reduction of MMP-2 and MMP-9 activities. The current in vitro study indicates that the inhibition of proliferation and invasion/migration in OSCC cell lines by ZD1839 results in an anticancer effect via multiple cellular and molecular mechanisms, and suggests that ZD1839 may be useful in inhibiting and/or preventing metastasis.

Original languageEnglish
Title of host publicationSignal Transduction Pathways, Part C
Subtitle of host publicationCell Signaling in Health and Disease
PublisherBlackwell Publishing Inc.
Pages113-128
Number of pages16
ISBN (Print)1573316954, 9781573316958
DOIs
Publication statusPublished - 2007 Jan 1

Publication series

NameAnnals of the New York Academy of Sciences
Volume1095
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Fingerprint

Matrix Metalloproteinases
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Squamous Cell Carcinoma
Cells
Cell Line
Cyclin-Dependent Kinases
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Cell Cycle
gefitinib
Epithelial Cells
Invasion
Up-Regulation
Quinazolines
G1 Phase Cell Cycle Checkpoints
Frameshift Mutation
Mouth Neoplasms
Polymerase chain reaction
Enzyme activity

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Eun, J. L., Jin, H. W., Nam, K. J., & Kim, J. (2007). The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. In Signal Transduction Pathways, Part C: Cell Signaling in Health and Disease (pp. 113-128). (Annals of the New York Academy of Sciences; Vol. 1095). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1397.015
Eun, Ju Lee ; Jin, Ha Whang ; Nam, Kyeong Jeon ; Kim, Jin. / The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. Signal Transduction Pathways, Part C: Cell Signaling in Health and Disease. Blackwell Publishing Inc., 2007. pp. 113-128 (Annals of the New York Academy of Sciences).
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abstract = "Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to characterize the effects of ZD1839 with regard to human OSCC cell growth and invasion/migration. The YD-10B cells represent a highly invasive human OSCC cell line, which has a frame shift p53 mutation. ZD1839 inhibited the growth of the cell line in a time- and dose-dependent manner. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest. This induction of a G1 cell cycle arrest was associated with the upregulation of cyclin-dependent kinase inhibitors (CDKI) p27KIP1 and p21CIP1/WAF1. The upregulation of CDKI in ZD1839 treated cell lines may be mediated by a p53-independent and hnRNPC1/C2-dependent pathway. In addition, 100 nM ZD1839 demonstrated that both MMP-2 and MMP-9 enzyme activity were decreased by ∼25-30{\%}. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that ZD1839 downregulated the uPAR mRNA level. These results might be associated with the reduction of MMP-2 and MMP-9 activities. The current in vitro study indicates that the inhibition of proliferation and invasion/migration in OSCC cell lines by ZD1839 results in an anticancer effect via multiple cellular and molecular mechanisms, and suggests that ZD1839 may be useful in inhibiting and/or preventing metastasis.",
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Eun, JL, Jin, HW, Nam, KJ & Kim, J 2007, The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. in Signal Transduction Pathways, Part C: Cell Signaling in Health and Disease. Annals of the New York Academy of Sciences, vol. 1095, Blackwell Publishing Inc., pp. 113-128. https://doi.org/10.1196/annals.1397.015

The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. / Eun, Ju Lee; Jin, Ha Whang; Nam, Kyeong Jeon; Kim, Jin.

Signal Transduction Pathways, Part C: Cell Signaling in Health and Disease. Blackwell Publishing Inc., 2007. p. 113-128 (Annals of the New York Academy of Sciences; Vol. 1095).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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AB - Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to characterize the effects of ZD1839 with regard to human OSCC cell growth and invasion/migration. The YD-10B cells represent a highly invasive human OSCC cell line, which has a frame shift p53 mutation. ZD1839 inhibited the growth of the cell line in a time- and dose-dependent manner. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest. This induction of a G1 cell cycle arrest was associated with the upregulation of cyclin-dependent kinase inhibitors (CDKI) p27KIP1 and p21CIP1/WAF1. The upregulation of CDKI in ZD1839 treated cell lines may be mediated by a p53-independent and hnRNPC1/C2-dependent pathway. In addition, 100 nM ZD1839 demonstrated that both MMP-2 and MMP-9 enzyme activity were decreased by ∼25-30%. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that ZD1839 downregulated the uPAR mRNA level. These results might be associated with the reduction of MMP-2 and MMP-9 activities. The current in vitro study indicates that the inhibition of proliferation and invasion/migration in OSCC cell lines by ZD1839 results in an anticancer effect via multiple cellular and molecular mechanisms, and suggests that ZD1839 may be useful in inhibiting and/or preventing metastasis.

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Eun JL, Jin HW, Nam KJ, Kim J. The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. In Signal Transduction Pathways, Part C: Cell Signaling in Health and Disease. Blackwell Publishing Inc. 2007. p. 113-128. (Annals of the New York Academy of Sciences). https://doi.org/10.1196/annals.1397.015