Hormones from the Heart Inhibit c-Jun andc-Fos proto oncogenes in Hepatocellular, Small-Cell Lung and Renal Carcinomas

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 303-321-Cancer in Endocrine Tissues
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-311
Neil J Manimala, Chelsea D Frost, Meghan L Lane, Mariana Higuera and David L Vesely*
James A. Haley VA Medical Center and University of South Florida Morsani School of Medicine, Tampa, FL
Hormones from the Heart Inhibit c-Jun and c-Fos proto oncogenes in Hepatocellular, Small-Cell Lung and Renal Carcinomas

 

Neil J. Manimala, Chelsea D. Frost, Meghan L. Lane, Mariana Higuera and David L. Vesely

Departments of Medicine, Molecular Pharmacology and Physiology, James A. Haley VA Medical Center, Tampa, Florida, and University of South Florida Morsani School of Medicine, Tampa, Florida

 

     c-Fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors. Transcription of c-Fos can induce hepatocellular carcinoma. c-Fos dimerizes with c-Jun oncogene to form AP-1 transcription factor, which upregulates transcription of genes involved in proliferation and cancer formation. Regulation of c-Fos is through the mitogen-activated protein kinase pathway and via signal transducer and activator of transcription-3 (STAT-3), which is a cytoplasmic transcription factor. c-Jun is activated through double phosphorylation by the JNK pathway and STAT-3. Four cardiac hormones, i.e., long-acting natriuretic peptide, vessel dilator, kaliuretic peptide, and atrial natriuretic peptide, have anticancer effects in vivo. They are potent inhibitors of the Ras-MEK 1/2-ERK 1/2 cytoplasmic kinase cascade that activate c-Fos, and they inhibit JNK-2, which activates c-Jun proto oncogene, which is the rationale to determine if the cardiac hormones can inhibit the proto-oncogenes c-Fos and c-Jun within nuclei of cancer cells. Our results indicate that the four cardiac hormones in dose response evaluations from 100 pM to 10 μM decrease up to 82% of c-Fos in human hepatocellular, small-cell lung cancer, and renal adenocarcinoma cells at their 10 μM concentrations. They were also found to decrease up to 65% of c-Jun in nuclear extracts of these three different types of cancer cells at their 10 μM concentrations. These results indicate that the cardiac hormones, which have previously been demonstrated to enter the nuclei of cancer cells, are potent inhibitors of proto-oncogenes within the nucleus. This first demonstration that any of the cardiac hormones can inhibit a proto oncogene and their ability to decrease c-Fos and c-Jun proto oncogenes suggests that they may inhibit the transcription of various genes involved in cancer formation.

Nothing to Disclose: NJM, CDF, MLL, MH, DLV

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Support: This work was supported in part by grants from the James and Esther King Florida Biomedical Research Program, the Florida Department of Health, and the Mama Mare Breast Cancer Foundation.   Disclosure: Dr. Vesely has assigned the patent to treat cancer with these cardiac hormones to the University of South Florida, which has not licensed this patent to any commercial entity. There has been no pharmaceutical company funding or input into the studies described herein.