Pyruvate kinase M2 (PKM2) is a key enzyme of glycolysis, which is highly expressed in many tumor cells, and has emerged as an important player in tumor progression and metastasis. However, the functional roles of PKM2 in tumor metastasis remain elusive. Here we showed that PKM2 promoted prostate cancer metastasis via extracellular-regulated protein kinase (ERK)-cyclooxygenase (COX-2) signaling. Based on public databases, we found that PKM2 expression was upregulated in prostate cancer and positively associated with tumor metastasis. Further analysis showed that PKM2 promoted prostate cancer cell migration/invasion and epithelial-mesenchymal transition (EMT) through upregulation of COX-2. Mechanistically, PKM2 interacted with ERK1/2 and regulated its phosphorylation, leading to phosphorylation of transcription factor c-Jun, downstream of ERK1/2, to activate COX-2 transcription by IP and ChIP assay, while inhibition of COX-2 significantly reversed the promotion effect of PKM2 on tumor metastasis in vivo. Taken together, our results suggest that a novel of PKM2-ERK1/2-c-Jun-COX-2 axis is a potential target in controlling prostate cancer metastasis.

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The effect of renal transplantation on bone mass.

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling.

The extent to which secondary hyperparathyroidism may involute remains poorly defined. Renal transplantation offers a clinical situation in which metabolic stimuli for hyperparathyroidism are removed. To examine whether hyperparathyroidism resolves after transplantation, we evaluated 11 renal transplant recipients who had been normocalcemic 6 or more months after transplantation using a sensitive 2-site immunoradiometric assay for intact serum PTH. Nine of the 11 had PTH concentrations within the normal range. Of these 9, 6 were found to have abnormal parathyroid function when challenged with an iv calcium infusion. The other 2 patients demonstrated significantly elevated basal PTH concentrations and elevated ionized calcium despite normal total serum calcium and albumin concentrations. In both, the PTH response to infused calcium was markedly abnormal, confirming hyperparathyroidism. The estimated renal threshold phosphate concentration was low in 4 of 9 patients with normal basal PTH concentrations and in both with elevated basal PTH. Bone mineral density, measured at the radius by single photon absorptiometry and at the spine by dual energy x-ray absorptiometry, was normal in 8 of the 9 transplant recipients who had normal basal PTH concentrations.

Parathyroid function in normocalcemic renal transplant recipients: evaluation by calcium infusion.

It is easy to review the literature on estrogens and bone disease in patients with chronic renal failure: a literature search revealed no articles which simultaneously considered estrogens, bones , and kidney failure. In fact, there are only a few recent articles about estrogen in dialysis patients. Since this subject was reviewed a decade ago (l), there has been little research interest in the effects of estrogen. Estrogen is rarely considered a pathophysiological factor in the development of renal osteodystrophy or coronary artery disease in women on dialysis, despite the fact that most of these women have abnormalities in the hypothalamic-pituitary control of ovarian function. Amenorrhea occurs in about 53% of these patients (1). The women are anovulatory with increased luteinizing hormone levels without an ovulatory surge. Follicle-stimulating hormone levels are normal, and estrogen levels are low to normal. These abnormalities are due to disturbances in the hypothalamic regulation ( 1 4 ) . In women with normal renal function, on the other hand, estrogen has been shown to be important in maintaining bone mass, particularly in the trabecular bone of the spine. Trabecular bone accounts for about 20% and cortical bone about 80% of bone mass; because trabecular bone has much greater surface area, it is the site of most metabolic activity. Fractures classically associated with osteoporosis are in skeletal sites that have greater amounts of trabecular bone, such as the spine, distal radius, and hip. There are several examples of estrogen deficiency which have been associated with bone loss. The common clinical finding in all these cases is irregular or absent menstruation. The most common cause of estrogen deficiency is natural menopause, during which women lose from 5% to 10% per year of their spinal trabecular bone. This loss can be avoided with estrogen replacement therapy. Patients with primary ovarian failure have spinal bone density 39% lower than that in controls; longitudinal and cross-sectional studies show improvement with estrogen treatment (5 ) . Women with secondary amenorrhea (6) or hypothalamic amenorrhea (7) show a reduction of spinal density of about 28%. Amenorrhea from hyperprolactinemia is associated with spinal bone density losses of 17% (7) to 25% (8). Young athletic women, at the peak of physical health, show dramatic bone losses if they

Does Estrogen Play a Role in Renal Osteodystrophy

Publisher Summary This chapter discusses the preventive measures that can reduce the risk of bone disease in candidates of organ transplant. In a high proportion of organ transplant recipients, metabolic abnormalities overwhelm the ability of the bone to respond to stress, which results in structural failure and fractures. Transplant recipients who don't appear to have many risk factors may nevertheless experience fractures, and those who do have “traditional” risk factors have an even greater chance of suffering from a fracture. Therefore, it is important to check these patients for both major and minor risk factors, and to correct those that are amenable to treatment. Because it is easier to prevent bone loss than it is to restore bone, optimization of factors that relate to bone health should be done as soon as possible. Transplant candidates frequently have multiple risk factors for bone fragility. These complex patients present a challenge to their physicians. In addition to the risk factors defined by epidemiological studies of the general population, the transplant candidates have risk factors depending on which organ has failed. Therapeutic choices may be limited or ineffective, and side effects may be more pronounced. Definitive studies on the benefits of preventive treatment in transplant candidates are lacking. Attention to all the cumulative risk factors and treatment within the available options will hopefully result in stronger bones with fewer fractures.

Management of Bone Disease in Candidates for Organ Transplant

本研究では腎移植と透析療法間における骨代謝に対する影響の違いを調べる目的にて, radiographic absorptiometryの一方法であるdigital image processing method (DIP法) を用いて測定した骨塩量および骨代謝パラメーターを腎移植患者と透析患者間において比較検討した.対象は山口大学泌尿器科にて経過観察中で移植後6か月以上経過し移植腎機能良好な腎移植患者27名 (腎移植群) と, 岩国中央病院にて血液透析施行中の透析患者26名 (透析群) であり, 年齢, 性別, 治療期間には両群間において有意差を認めなかった. 各群における骨塩量 (ΣGS/D, MCI) と各骨代謝パラメーターとの相関をみると, 腎移植群においては有意な相関関係は認めなかったが, 透析群においてはΣGS/Dと透析期間, Al-P, またMCIと透析期間, C-PTH, Al-Pとの間にそれぞれ有意な相関関係を認めた.両群間での骨塩量の比較では, ΣGS/Dは腎移植群では2.61±0.33mmAl, 透析群では2.30±0.52mmAlであり, 腎移植群において有意に高値であった (p<0.05). MCIは腎移植群では0.352±0.083, 透析群では0.343±0.072であり, 両群間に有意差は認めなかった. さらに移植歴または透析歴5年以上の長期subgroup間での比較では, ΣGS/Dは長期腎移植群では2.56±0.25mmAl, 係は認めなかったが, 透析群においてはGS/Dと透析期間, Al-P, またMCIと透析期間, C-PTH, Al-Pとの間にそれぞれ有意な相関関係を認めた.両群間での骨塩量の比較では, ΣGS/Dは腎移植群では2.61±0.33mmAl, 透析群では2.30±0.52mmAlであり, 腎移植群において有意に高値であった (p<0.05). MCIは腎移植群では0.352±0.083, 透析群では0.343±0.072であり, 両群間に有意差は認めなかった. さらに移植歴または透析歴5年以上の長期subgroup間での比較では, ΣGS/Dは長期腎移植群では2.56±0.25mmAl, 長期透析群では2.07±0.46mmAlであり, 長期腎移植群において有意に高値であった (p<0.01). また男女別subgroup間における比較では, ΣGS/D, MCIともに両群間に有意差は認めなかったが, 閉経後女性を除いたsubgroup間での比較において透析群女性のΣGS/Dが有意に低値であった (p<0.05).以上のことからDIP法を用いた検討では, 透析患者の骨塩量は腎移植患者に比べ低下しており, 原因として二次性副甲状腺機能亢進症の影響を受けている可能性が示唆された.

The effect of renal transplantation on bone mass.

Citations

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling.

Parathyroid function in normocalcemic renal transplant recipients: evaluation by calcium infusion.

Does Estrogen Play a Role in Renal Osteodystrophy

Management of Bone Disease in Candidates for Organ Transplant

A comparison of bone mineral density analyzed by a digital image processing method in renal transplant recipients and hemodialysis patients