Suppression of growth of H-69 small cell lung carcinoma by antagonists of growth hormone releasing hormone and bombesin is associated with an inhibition of protein kinase C signaling.
We investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone and in combination with bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on the growth of H-69 human small cell lung carcinoma (SCLC) xenografted into nude mice. Since the activation of the signaling pathways involving protein kinase C (PKC) and the subsequent steps involving mitogen-activated protein kinase (MAPK) and c-fos and c-jun oncogenes are known to be important mechanisms implicated in cellular growth, we investigated how the blockade of tumoral GHRH receptor splice variants and BN/GRP receptors by these antagonists could interfere with these intracellular signaling pathways. Treatment with GHRH antagonists JV-1-65 or MZ-J-7-110 for 4 weeks significantly (p<0.05) decreased the tumor volume by 22.7+/-3.0% and 36.7 +/- 3.6%, respectively, as compared to controls. A larger decrease in tumor volume of 73.0 +/- 9.5% (p<0.01) was produced by BN/GRP antagonist RC-3940-II and its combination with JV-I-65 caused the greatest tumor reduction of 91.0 +/- 9.8% (p<0.01) vs. controls. H-69 SCLC tumors expressed alpha-, betaII-, delta- and eta-PKC isoforms. Antagonists of GHRH and BN/GRP decreased significantly (p<0.05) the expression of betaII- and delta-, but not of alpha- and eta-PKC isoforms. They also inhibited MAPK levels, the effects being significant (p<0.05) in the groups that received BN/GRP antagonist. In addition, expression of c-fos and c-jun mRNA was reduced after combined treatment with JV-1-65 and RC-3940-II. The proliferation of H-69 SCLC cells "in vitro" was also significantly inhibited after incubation of cells with GHRH antagonist, PKC inhibitors or MAPK inhibitor. These findings suggest that the anti-proliferative effects of antagonists of GHRH and BN/GRP on H69-SCLC involve an inhibition of the signaling pathways of specific PKC isoforms, MAPK and c-fos and c-jun oncogenes.
Kanashiro
Celia A
CA
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
Schally
Andrew V
AV
Zarandi
Marta
M
Hammann
Brian D
BD
Varga
Jozsef L
JL
D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000503:physiopathology*; D002455:Cell Division; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000494:pharmacology; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D013007:Growth Hormone-Releasing Hormone; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D001839:Bombesin