Proteasome inhibitors induce apoptosis in some malignant cells, and we show here that these inhibitors induce apoptosis in rat pituitary MMQ and GH3 tumor cells but not in normal pituitary cells. Three proteasome inhibitors, PSI, MG-132, and lactacystin, but not the calpain inhibitor, ALLM, dose- and time-dependently caused apoptosis in these cells, and 10 microM PSI caused apoptosis in 70% of MMQ cells and in 25% of GH3 cells within 24 h. A lower PSI dose (10 nM) inhibited GH3 cell growth without causing significant apoptosis or affecting prolactin secretion. Primary rat pituitary cells were resistant to both PSI and MG-132 and did not undergo apoptosis. In MMQ cells, DNA synthesis was slowed (approximately 30%) after 6 h of 10 microM PSI treatment and a partial cell cycle block at G2/M was evident after 8 h. Colorimetric caspase substrate assay and Western blotting of caspase substrates showed that caspases 2 and 3 are activated by PSI while caspases 6 and 8 remained inactive. A broad-range caspase inhibitor, caspase inhibitor III, prevented apoptosis induced by PSI. The results show that proteasome inhibitors induce apoptosis in rat pituitary tumor cells by specific caspase activation. This novel group of drugs may potentially be used in treatment of aggressive pituitary tumors, especially as their action appears relative for tumor cells.
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R Yu, SG Ren, and S Melmed
M Fraenkel, J Caloyeras, S-G Ren, and S Melmed
Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced post-natal -cell proliferation and an inability to expand islet cell mass with aging. We therefore examined the effects of sex-steroid manipulation on diabetes development in pttg −/− male mice. Surgical gonadectomy was followed by implantation of 90-day slow-release pellets releasing 17β-estradiol (0.36 mg/pellet), placebo or dihydrotestosterone (DHT; 12.5 mg/pellet). Mean fasting blood sugars at the end of the study were 414 ± 54 mg/dl for pttg −/− controls and 371 ± 14 mg/dl for pttg −/− mice gonad-ectomized and treated with DHT compared with 124 ± 40 and 85 ± 12 mg/dl in gonadectomized pttg −/− males treated with placebo or estradiol, respectively (P < 0.01 compared with control pttg −/−). Gonadectomy with and without estradiol treatment did not increase the very low circulating insulin levels in pttg-null males (fasting insulin 0.44 ± 0.04 ng/ml in pttg −/− controls, 0.47 ± 0.07 and 0.4 ng/ml in pttg −/− gonadectomized males treated with placebo or estradiol, respectively). Gonadectomy increased serum adiponectin levels (4.9 ± 008 μg/ml in pttg −/− controls versus 13 ± 0.08 and 7.5 ± 0.6 μg/ml in pttg −/− gonadectomized males treated with placebo or estradiol, respectively; P < 0.001 and P < 0.05), accompanied by increased insulin sensitivity. The results show that gonadectomy delayed, and gonadectomy with additional estradiol treatment prevented, diabetes development in pttg −/− males, possibly through increased insulin sensitivity mediated by elevated serum adiponectin levels. Male-selective effects of disrupted β-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.