Pro-opiomelanocortin gene delivery suppresses the growth of established Lewis lung carcinoma through a melanocortin-1 receptor-independent pathway

Background Pro-opiomelanocortin (POMC) is the precursor of several neuropeptides, such as corticotropin, melanocyte-stimulating hormone and the endogenous opioid (beta-endorphin). Our previous studies have indicated that POMC gene delivery inhibited the progression and metastasis of B16-F10 melanoma via the alpha- melanocyte-stimulating hormone/melanortin-1 receptor (MC-1R) pathway. Methods In the present study, the therapeutic efficacy of POMC gene therapy was evaluated in mice bearing established Lewis lung carcinoma (LLC) models both in vitro and in vivo. We also investigated the MC-1R-independent mechanism underlying POMC gene therapy. Results We found that POMC gene delivery significantly inhibited the growth and colony formation in MC-1R-deficient LLC cells. In addition, POMC gene transfer effectively suppressed the growth of established LLC in mice. The inhibitory-mechanisms underlying POMC gene delivery were attibuted to be inhibition of proliferation and the induction of apoptosis. Moreover, POMC gene delivery attenuated tumor beta-catenin signaling by reducing protein levels of beta-catenin and its downstream proto-oncogenes, including cyclin D1 and c-myc. Lastly, POMC gene delivery induced a significant suppression of tumor vasculature. Conclusions These results support the existence of an MC-1R-independent pathway for POMC gene therapy, which further expands the therapeutic spectrum of POMC therapy for multiple types of cancer. Copyright (C) 2012 John Wiley & Sons, Ltd.