| Some individuals with autosomal dominant isolated growth hormone deficiency have one copy of a growth hormone gene that lacks amino acids 32 through 71 (d32-71-hGH). Transient expression of d32-71-hGH in neuroendocrine cells causes a 50% decrease in the secretion of wildtype human growth hormone (wt-hGH) that results from a decrease in the stability of wt-hGH (Lee, et al., 2000). D32-71-hGH was not toxic to non-ovarian cell lines like COS-7 (green monkey kidney cell line), GH4C1 (rat pituitary cell line), 293 (human kidney cell line), or AtT-20 (mouse pituitary cell line) cells in transient transfections; however, we provide evidence that d32-71-hGH is toxic to Hey cells, an ovarian carcinoma cell line. This is the first report of a misfolded protein that confers toxicity in a cell type-specific manner.; We show that in Hey cells and COS-7 cells, d32-71-hGH accumulates, but fails to induce the unfolded protein response, assessed by induction of BiP, a endoplasmic reticulum chaperone protein. When d32-71-hGH accumulates, it interferes with the secretion of secreted alkaline phosphatase by Hey cells, and to a lesser extent by COS-7 cells. We also found that d32-71-hGH resulted in the altered trafficking of proteins like thyrotropin-releasing hormone receptor, βeta-coatomer protein, and prolactin in COS-7 cells, and prolactin in Hey cells. In addition to altered trafficking and secretion of other proteins, d32-71-hGH resulted in decreased synthesis of human prolactin in Hey cells, but did not affect synthesis of human prolactin in COS-7 cells. We also observed that d32-71-hGH results in the disruption of the Golgi apparatus in COS-7 cells, but not Hey cells.; A model consistent with our findings is that d32-71-hGH is toxic in Hey cells, but is not toxic in COS-7 cells, because accumulation of the mutant in the endoplasmic reticulum decreases the secretion of other proteins more effectively in Hey cells. Failure of traditional approaches to treating ovarian cancer warrants new approaches to this disease. D32-71-hGH can perhaps improve therapy for this cancer by targeting the secretory pathway of ovarian cancer cells. |
