Nanoliposomal short-chain ceramide inhibits agonist-dependent translocation of neurotensin receptor 1 to structured membrane microdomains in breast cancer cells.

Neurotensin (NTS) receptor 1 (NTSR1) is a G protein-coupled receptor that has been recently identified as a mediator of tumorigenicity and metastasis. NTSR1, as well as its endogenous ligand, NTS, are coexpressed in several breast cancer cell lines and breast cancer tumor samples but not in normal breast tissue. We have previously published that ceramide mimetics could inhibit breast cancer growth in vitro and in vivo. Thus, understanding the biochemical and biophysical regulation of NTSR1 by ceramide can help further define NTSR1 as a novel target in breast cancer. Our results show that nanoliposomal formulations of ceramide inhibit NTSR1-mediated MDA-MB-231 breast cancer progression (mitogenesis, migration, and matrix metalloproteinase-9 activity). In addition, liposomal ceramide inhibited NTSR1-mediated, but not phorbol 12-myristate 13-acetate-mediated, activation of the mitogen-activated protein kinase pathway. Mechanistically, nanoliposomal short-chain ceramide reduces NTSR1 interaction with Galphaq/11 subunits within structured membrane microdomains, consistent with diminished NTS-induced translocation of NTSR1 into membrane microdomains. Collectively, our findings suggest that exogenous short-chain ceramide has the potential to be used as an adjuvant therapy to inhibit NTS-dependent breast cancer progression.