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Center for Endocrinological Oncology, Department of Endocrinology (P.L., R.M.M., M.M.M., D.D., M.M.), and Department of Medical Pharmacology (M.P.), University of Milano, 20133 Milano, Italy
Address all correspondence and requests for reprints to: Dr. P. Limonta, Center for Endocrinological Oncology, Department of Endocrinology, Via Balzaretti 9, 20133 Milano, Italy. E-mail: limonta{at}mailserver.unimi.it
Evidence has accumulated indicating that LHRH might behave as an
autocrine/paracrine growth inhibitory factor in some peripheral tumors.
However, LHRH receptors in tumor cells have not been fully
characterized, so far. The present experiments were performed to
analyze: 1) the messenger RNA expression; 2) the molecular size;
and 3) the signal transduction pathway of LHRH receptors in prostate
cancer. For these studies, the human androgen-dependent LNCaP and
androgen-independent DU 145 prostate cancer cell lines were used.
1) By RT-PCR, a complementary DNA product, which hybridized with
a 32P-labeled oligonucleotide probe specific for the
pituitary LHRH receptor complementary DNA, was found both in LNCaP and
in DU 145 cells. 2) Western blot analysis, using a monoclonal antibody
raised against the human pituitary LHRH receptor, revealed the presence
of a protein band of approximately 64 kDa (corresponding to the
molecular mass of the pituitary receptor) in both cell lines. 3) In
LNCaP and DU 145 cells, pertussis toxin completely abrogated the
antiproliferative action of a LHRH agonist (LHRH-A). Moreover, LHRH-A
substantially antagonized the pertussis toxin-catalyzed
ADP-ribosylation of a G
i protein. Finally, LHRH-A
significantly counteracted the forskolin-induced increase of
intracellular cAMP levels in both cell lines. These data demonstrate
that the LHRH receptor, which is present in prostate cancer cells,
independently of whether they are androgen-dependent or not,
corresponds to the pituitary receptor, in terms of messenger RNA
expression and protein molecular size. However, at variance with the
receptor of the gonadotrophs, prostate cancer LHRH receptor seems
to be coupled to the Gi protein-cAMP signal transduction
pathway, rather than to the Gq/11-phospholipase C
signaling system. This might be responsible for the different actions
of LHRH in anterior pituitary and in prostate cancer.
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