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

✍ Scribed by Celia A. Kanashiro; Andrew V. Schally; Marta Zarandi; Brian D. Hammann; Jozsef L. Varga

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: French
• Weight: 178 KB
• Volume: 112
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.20437

✦ Synopsis

Abstract

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 α‐, βII‐, δ‐ and η‐PKC isoforms. Antagonists of GHRH and BN/GRP decreased significantly (p<0.05) the expression of βII‐ and δ‐, but not of α‐ and η‐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. © 2004 Wiley‐Liss, Inc.