UC San Diego

Lung cancer has one of the highest death rates of all human cancers with non-small cell lung carcinomas (NSCLC) making up the majority of diagnoses. NSCLC tumor products include parathyroid hormone-related protein (PTHrP), an oncoprotein known to cause hypercalcemia and other cancer side effects. The full length PTHrP protein is capable of being cleaved into several daughter peptides, including the portion resembling parathyroid hormone, amino PTHrP 1- 34. The amino PTHrP peptide is a negative prognostic indicator; patients have shorter survival if their tumors express higher levels of it or its cognate receptor, PTH1R. Amino PTHrP expression has been discovered to be less frequent in tumors of male NSCLC patients compared to females, but the reasons are unknown. It was our hypothesis that androgens negatively regulated amino PTHrP, explaining the lower expression in males. To test this, we treated BEN human squamous lung carcinoma cells, both with and without transfected androgen receptor (AR), with exogenous testosterone, dihydrotestosterone, and R1881, then measured amino PTHrP 1-34 by ELISA. None of the three androgens significantly affected BEN cell amino PTHrP. However, 5[alpha]-Androstane-3[alpha],17[Beta]-diol (3[alpha]-diol), a metabolite of dihydrotestosterone that is produced robustly by lung cancer cells, caused significant time- and dose-dependent decreases in amino PTHrP levels. These effects were independent of ectopic overexpression of AR and were enhanced when enzymes regulating 3[alpha]-diol levels were inhibited. These results show that 3[alpha]-diol is capable of lowering the expression of amino PTHrP 1-34 by AR independent pathways in NSCLC