Cancers of the lungs and head and neck are one of the leading causes of death, particularly in Kentucky, which leads the nation in multiple categories related to smoking. Thus, there is an urgent need for new biomarkers and therapeutic targets for airway cancers. The sigma-2 receptor is an intracellular receptor for numerous drugs and metabolites and was recently found to be identical to Pgrmc1 (progesterone receptor membrane component 1), a cytochrome-related protein implicated in metabolism and hormone signaling. S2RPgrmc1 is up-regulated in multiple types of cancer and is required for tumor cell proliferation and motility in vitro and tumor formation and metastasis in vivo. Furthermore, small molecule inhibitors of S2RPgrmc1 suppressed the growth of lung, breast and cervical cancer cell lines. In the present study, we have analyzed S2RPgrmc1 levels in clinical tumor samples from squamous cell lung cancers (SqCLC), lung adenocarcinomas, head and neck cancers and others. S2RPgrmc1 levels were increased in tumors throughout and correlated with survival in lung cancer (n=43, p=0.02) and with grade in head and neck cancer (higher in grade 2 versus 1, p=0.007). One of the cancer types with highest S2RPgrmc1 expression was squamous cell lung cancer (SqCLC), and treatment options for SqCLC are limited. S2RPgrmc1 was highly expressed in SqCLC cell lines, and SqCLC cell survival was inhibited by siRNA knockdown of S2RPgrmc1 or the S2RPgrmc1 inhibitor AG-205. S2RPgrmc1 is part of a family of secreted cytochromes, and we found that S2RPgrmc1 was significantly elevated in the plasma of 42 lung cancer patients compared to non-cancer patients and was significantly higher in the plasma of stage I lung cancer patients compared to stage 2-4 patients. Purified, recombinant S2RPgrmc1 increased the proliferation of NSCLC cell lines, suggesting that secreted S2RPgrmc1 may contribute to lung tumor growth. Together, the results demonstrate that S2RPgrmc1 correlates with key clinical endpoints in tumors and is a therapeutic target in some cancers with few therapeutic options, particularly squamous cell lung cancer. Furthermore, S2RPgrmc1 is a potential plasma biomarker for early stage lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3604. doi:1538-7445.AM2012-3604