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.
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.
Huang
Ying-Tang
YT
Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
Hwang
Jiuan-Jiuan
JJ
Lee
Lung-Ta
LT
Liebow
Charles
C
Lee
Ping-Ping H
PP
Ke
Ferng-Chun
FC
Lo
Tung-Bin
TB
Schally
Andrew V
AV
Lee
Ming-Ting
MT
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D053938:DNA Fragmentation; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011233:Precipitin Tests; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D017329:Triptorelin Pamoate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D017329:Triptorelin Pamoate; D013912:Threonine; D007987:Gonadotropin-Releasing Hormone; D012694:Serine; D004815:Epidermal Growth Factor; D017027:Protein Tyrosine Phosphatases; D020169:Caspases; D020782:Matrix Metalloproteinases