Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75-IP3R-Ca2+-AMPK Axis.

Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.

Dietary acid-base balance, bone resorption, and calcium excretion.

OBJECTIVE: Metabolic studies reveal that acidogenic diets increase bone resorption acutely. This study was conducted to examine associations between diet-induced changes in net acid excretion (NAE) and changes in serum parathyroid hormone (PTH), bone resorption, and calcium excretion over a longer period of 60 days. METHODS: Forty healthy older men and women were given 0.75 g/kg of protein as meat, 600 mg of calcium, and 400 IU of vitamin D3 daily and either cereal (acidogenic) or fruit and vegetable (alkalinogenic) foods as substitutes for some of the cereal in their usual diets. Blood and 24-hr urine measurements were made on days 14 (baseline), 44, and 74. RESULTS: In all subjects, change in renal NAE was correlated with changes in serum PTH (r = 0.358, P = 0.023), urinary N-telopeptide (NTX) (r = 0.367, P = 0.020), and urinary calcium excretion (rp = 0.381, P = 0.020, after adjustment for diet group, change in PTH, and change in sodium excretion). CONCLUSIONS: Diet changes that increase renal NAE are associated with increases in serum PTH, bone resorption, and calcium excretion over a 60-day period.

Lack of effect of calcium intake on the 25-hydroxyvitamin d response to oral vitamin D3.

This study was conducted to examine the effect of calcium intake on the rise in serum 25-hydroxyvitamin D [25(OH)D] levels in response to supplemental vitamin D(3). Fifty-two healthy older men and women were randomly assigned to take calcium (500 mg twice daily with meals) or placebo tablets for 90 d between October 1 and the end of March. All participants were placed on 800 IU/d (20 microg/d) vitamin D(3). Serum 25(OH)D measurements were made at baseline and on d 30, 60, and 90. The mean baseline 25(OH)D values were 19.2 +/- 6.4 ng/ml (47.9 +/- 15.9 nmol/liter) in the calcium group and 19.6 +/- 6.7 ng/ml (49.1 +/- 16.7 nmol/liter) in the control group (P = 0.808). The difference in pattern of change in 25(OH)D was not statistically significant (group by time interaction, P = 0.651); the calcium group increased 6.5 +/- 5.9 ng/ml (16.2 +/- 14.8 nmol/liter; P < 0.001), and the control group increased 6.6 +/- 7.0 ng/ml (16.6 +/- 17.4 nmol/liter; P < 0.001). The 95% confidence interval for difference in mean increase, calcium vs. control, was -3.8 +/- 3.5 ng/ml (-9.6, 8.7) nmol/liter. In older men and women, the level of calcium intake, within the range of 500-1500 mg/d, does not have an important effect on the rise in serum 25(OH)D that occurs in response to 800 IU (20 microg)/d vitamin D(3).

Calcium supplement and osteoporosis medication use in women and men with recent fractures.

Patients with low-trauma fractures are at risk of future fractures and so should be evaluated and treated for osteoporosis. This study was conducted to assess and compare bone medication use and calcium and vitamin D intake at the time of and after an acute fracture. One hundred and six patients, mean age 66.7+/-10.3 years, were administered medical history and diet questionnaires at enrollment (in an urban hospital) and again 6 and 12 months later (by telephone). Of 86 patients who could be contacted 6 months after their fracture, 36.2% of the women and 7.4% of the men had recently discussed osteoporosis with their primary care doctor. At 6 months, 24.2% of the women and 3.6% of the men were taking bone medications (compared with 27.8% and 3.6% before the fracture; NS). At 6 months, 52.6% of the women and 10.7% of the men indicated that their doctor had recently recommended calcium or vitamin D. Among the women who had recently been advised by their primary care doctor to use calcium or vitamin D, supplement use increased from 63.3% to 90.0% (P = 0.021) and dairy food intake increased from 1.5+/-1.1 to 2.4+/-1.9 servings/day (P = 0.016). Only three men received this advice and two of them heeded it. Among women and men not receiving this advice, there was no significant increase in calcium supplement use or dairy food intake. At 12 months, the treatment profiles were unchanged from 6 months and 9.6% of the women and 4.3% of the men had had another fracture. In conclusion, the occurrence of a fracture did not increase likelihood of pharmacologic treatment for osteoporosis. After their fractures, the women did increase their intake of calcium supplements and dairy foods when this was recommended by their doctor. This suggests that the primary care physician is well positioned to bring about much needed change in the quality of care of fracture patients.

Effect of dietary protein supplements on calcium excretion in healthy older men and women.

Currently there is no consensus on the impact of dietary protein on calcium and bone metabolism. This study was conducted to examine the effect of increasing protein intake on urinary calcium excretion and to compare circulating levels of IGF-I and biochemical markers of bone turnover in healthy older men and women who consumed either a high or a low protein food supplement for 9 wk. Thirty-two subjects with usual protein intakes of less than 0.85 g/kg.d were randomly assigned to daily high (0.75 g/kg) or low (0.04 g/kg) protein supplement groups. Isocaloric diets were maintained by advising subjects to reduce their intake of carbohydrates. Selected biochemical measurements were made at baseline and on d 35 and either d 49 or 63. Changes in urinary calcium excretion in the two groups did not differ significantly over the course of the study. The high protein group had significantly higher levels of serum IGF-I (P = 0.008) and lower levels of urinary N-telopeptide (P = 0.038) over the period of d 35-49 or 63. We conclude that increasing protein intake from 0.78 to 1.55 g/kg.d with meat supplements in combination with reducing carbohydrate intake did not alter urine calcium excretion, but was associated with higher circulating levels of IGF-I, a bone growth factor, and lowered levels of urinary N-telopeptide, a marker of bone resorption. In contrast to the widely held belief that increased protein intake results in calcium wasting, meat supplements, when exchanged isocalorically for carbohydrates, may have a favorable impact on the skeleton in healthy older men and women.