UC San Diego

Parathyroid hormone-related protein (PTHrP) is expressed in many tissues and is often enriched in cancers. Tissue reaction to PTHrP varies as it is expressed as multiple isoforms, undergoes peptide processing, and has selective trafficking. PTHrP is secreted via a pre-pro -36 to -1 amino acid portion and interacts with extracellular receptors, including parathyroid hormone receptor 1 (PTH1R). PTHrP is also present within the cell and shuttles into and out of the nucleus via a nuclear localization signal (NLS) and a nuclear export signal (NES). Patients diagnosed with non-small cell lung carcinomas that express PTHrP, experience higher survival rates. PTHrP's benefits in non-small cell lung cancer may result from its previously demonstrated anti-proliferative effects. Because of PTHrP's highly intricate actions, its site of inhibitory action on proliferation is not known. This project experimentally isolated the site of action and likely receptor responsible for PTHrP's inhibition on H1944 cells, an adenocarcinoma cell line. Early experimental results suggested that exogenous PTHrP has at least a partial role in growth inhibition. We successfully demonstrated that the nuclear trafficking of PTHrP is not necessary for inhibition of proliferation. We showed that PTHrP peptide introduced into the cell has no major effects on proliferation. Finally, we demonstrated that exogenous PTHrP treatments have the potential to inhibit proliferation at levels near stably transfected lines and that PTHrP does not inhibit cells with PTH1R knocked down. Based on these results we conclude that PTHrP inhibits proliferation of H1944 cells in an extracellular fashion dependent on the PTH1R