INDUCTION OF GASTRIN-RELEASING PEPTIDE BY ALL-TRANS-RETINOIC ACID IN SMALL-CELL LUNG-CANCER CELLS

All-trans retinoic acid (RA) has been shown to inhibit cell proliferat ion while increasing neuroendocrine differentiation in small cell lung cancer (SCLC) cells. RA and related compounds are rapidly becoming in tegrated into clinical trials to prevent lung cancers and other aerodi gestive neoplasms. We found that expression of gastrin releasing pepti de (GRP), which can promote lung tumorigenesis in model systems, was i ncreased by RA in SCLC cells which have functional retinoid signaling. In SCLC cells that possess functional GRP receptors, ectopic expressi on of RAR gamma increased GRP expression and augmented cloning efficie ncy, demonstrating that these maneuvers result in biologically active GRP. SCLC cells with defects in RA pathway signaling did not efficient ly induce GRP upon RA exposure. In these cells, transfection of RARs r endered the cells competent to induce GRP upon RA exposure. These data show that activation of intact retinoid signaling by RA can induce GR P, a growth factor that can act as a tumor promoter. Our findings sugg est the possibility that retinoids may increase, rather than decrease, lung cancer risks in some individuals.