Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A.
Endometrial cancer (EC) is a hormone-dependent cancer that currently represents the most frequent malignancy of the female reproductive tract. The involvement of steroid hormones in its etiology and progression has been reported. The possibility that even gonadotropins (GT) could play a role in the genesis and establishment of EC is supported by the fact that specific receptors for the GT luteinizing hormone/human chorionic GT (LH/hCG) have been detected in a high percentage of ECs, and their expression is apparently related to the cancer grading. However, the precise mechanisms by which GTs might exert their effect on EC is still obscure. The aim of this study was to determine the effects of LH/hCG on the invasion potential of EC cell lines and primary human EC cells. Human recombinant (hr) LH (and hCG) induced a significant increase in cell invasiveness through Matrigel-coated porous membranes in an EC human cell line Hec1A, which expresses the LH/hCG receptor. This effect turned out to depend on hrLH binding to its specific receptors and to the subsequent activation of protein kinase A (PKA). Moreover the hrLH-induced increase in Hec1A invasiveness relied upon a PKA-dependent functional activation of beta(1) integrin receptors, as well as the subsequent induction of matrix metalloproteinase-2 secretion in its active form. The same mechanisms were also found to be operative in primary EC cells. In fact, a significant percentage of primary ECs expressed the LH/hCG receptor, and hrLH addition to primary EC cells, which expressed the specific receptors produced an increase in cell invasiveness only in those tumor cells possessing the specific receptors. This effect was also dependent on PKA activity. We conclude that LH/hCG can regulate EC cells invasiveness, and this result provides a rationale for the use of inhibitors of LH secretion such as GnRH analogues in the treatment of EC.
Dabizzi
Sara
S
Department of Gynaecology, University of Firenze, 50134 Firenze, Italy.
Noci
Ivo
I
Borri
Patrizia
P
Borrani
Elena
E
Giachi
Massimo
M
Balzi
Manuela
M
Taddei
Gian Luigi
GL
Marchionni
Mauro
M
Scarselli
Gian Franco
GF
Arcangeli
Annarosa
A
D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007986:Luteinizing Hormone / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D007986:Luteinizing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases