Inhibitory effects of a luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associated properties in human epidermoid carcinoma A431 cells

Int J Cancer. 2002 Jun 1;99(4):505-13. doi: 10.1002/ijc.10373.

Abstract

The purpose of this study was to investigate the effects of a potent LHRH agonist, [D-Trp(6)]LHRH on the basal and EGF-induced cell proliferation and the metastasis-associated properties in A431 human epidermoid carcinoma. [D-Trp(6)]LHRH time-dependently inhibited the basal and EGF-stimulated growth of A431 cancer cells. It is assumed that phosphorylation/dephosphorylation of cellular proteins is highly related to cell growth. This study demonstrates that [D-Trp(6)]LHRH decreased the basal and EGF-induced total cellular kinase activity, particularly the tyrosine phosphorylation of several cellular proteins including the EGFR. In contrast, [D-Trp(6)]LHRH did not cause detectable changes in basal and EGF-stimulated serine/threonine phosphorylation of A431 cellular proteins. The inhibitory effect of [D-Trp(6)]LHRH on A431 cell proliferation was associated with apoptosis as evidenced by the cell morphology and DNA integrity (ladder pattern), the expression of interleukin 1beta-converting enzyme (ICE) and activation of caspase. Furthermore, EGF could rescue the remaining attached A431 cells following [D-Trp(6)]LHRH treatment for 48 hr, which suggests that limited exposure to [D-Trp(6)]LHRH did not channel all cells to irreversible apoptotic process. We also determined the effects of [D-Trp(6)]LHRH on metastasis-associated properties in A431 cells. [D-Trp(6)]LHRH reduced both basal and EGF-stimulated secretion of MMP-9 and MMP-2. In addition, [D-Trp(6)]LHRH suppressed the basal and EGF-induced invasive activity of A431 cells based on an in vitro invasion assay. In conclusion, this study indicates that [D-Trp(6)]LHRH may act partly through activating tyrosine phosphatase activity to inhibit cell proliferation and the metastasis-associated properties of A431 cancer cells. Our work suggests that [D-Trp(6)]LHRH may be therapeutically useful in limiting the tumor growth and metastasis of some neoplasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Carcinoma, Squamous Cell / metabolism*
  • Caspases / metabolism
  • Cell Division
  • DNA Fragmentation
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • Gonadotropin-Releasing Hormone / agonists*
  • Gonadotropin-Releasing Hormone / metabolism*
  • Humans
  • Immunoblotting
  • Matrix Metalloproteinases / metabolism
  • Neoplasm Invasiveness
  • Phosphorylation
  • Precipitin Tests
  • Protein Tyrosine Phosphatases / metabolism
  • Serine / metabolism
  • Threonine / metabolism
  • Time Factors
  • Triptorelin Pamoate / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Hormonal
  • Triptorelin Pamoate
  • Threonine
  • Gonadotropin-Releasing Hormone
  • Serine
  • Epidermal Growth Factor
  • Protein Tyrosine Phosphatases
  • Caspases
  • Matrix Metalloproteinases