Androgen-dependent prostatic tumors: biosynthesis and possible actions of LHRH.

Testosterone (T) is the major exogenous stimulus for the growth of prostatic carcinoma. It is believed that the proliferative action of T may be mediated by locally expressed growth modulatory factors. Recent evidence from our laboratory suggests that a LHRH (or a LHRH-like) loop might be expressed in human prostatic tumor cells. To verify this hypothesis, we have studied whether a mRNA for LHRH is expressed in the human androgen-responsive prostatic cancer cell line LNCaP, using the reverse transcription-polymerase chain reaction technique in the presence of a pair of specific oligonucleotide primers. A cDNA band of the expected size was obtained from LNCaP cells; this band hybridized with a 32P-labeled LHRH oligonucleotide probe and its sequence showed a complete match with the reported sequence of the human placental LHRH cDNA. These observations indicate that the mRNA coding for LHRH is expressed in LNCaP cells and suggest that a LHRH (or a LHRH-like) peptide might be produced by these cells. To clarify the possible action of this peptide, LNCaP cells were grown in a steroid-free medium and treated with a LHRH antagonist. The treatment resulted in a significant increase of tumor cell growth. These data clearly indicate that the LHRH system expressed in LNCaP cells plays an inhibitory role on cell proliferation, and that this system seems to be regulated in a negative way by steroids. An EGF/TGF alpha autocrine stimulatory loop (peptides, receptors, intracellular signals) is also functional in these cells. Treatment of LNCaP cells grown in serum-free conditions (i.e. in the absence of exogenous growth factors) with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF or TGF alpha, resulted in a significant decrease of cell proliferation. T positively regulates this EGF/TGF alpha system by increasing the concentration of EGF binding sites. The present data indicate that an inhibitory LHRH (or LHRH-like) system is expressed in LNCaP cells and participates in the local mechanisms regulating tumor cell proliferation together with an EGF/TGF alpha stimulatory loop. Both systems appear to be modulated by T.