Metabolic Heterogeneity, Plasticity, and Adaptation to "Glutamine Addiction" in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase-ω-Amidase (Glutaminase II)] Pathway.

Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as "l-glutamine addiction", this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate.

The metabolic importance of the glutaminase II pathway in normal and cancerous cells.

In rapidly dividing cells, including many cancer cells, l-glutamine is a major energy source. Utilization of glutamine is usually depicted as: l-glutamine → l-glutamate (catalyzed by glutaminase isozymes; GLS1 and GLS2), followed by l-glutamate → α-ketoglutarate [catalyzed by glutamate-linked aminotransferases or by glutamate dehydrogenase (GDH)]. α-Ketoglutarate is a major anaplerotic component of the tricarboxylic acid (TCA) cycle.

The metabolic importance of the overlooked asparaginase II pathway.

The asparaginase II pathway consists of an asparagine transaminase [l-asparagine + α-keto acid ⇆ α-ketosuccinamate + l-amino acid] coupled to ω-amidase [α-ketosuccinamate + HO → oxaloacetate + NH]. The net reaction is: l-asparagine + α-keto acid + HO → oxaloacetate + l-amino acid + NH. Thus, in the presence of a suitable α-keto acid substrate, the asparaginase II pathway generates anaplerotic oxaloacetate at the expense of readily dispensable asparagine.

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in 'Glutamine Addiction'.

Many tumors readily convert l-glutamine to α-ketoglutarate. This conversion is almost invariably described as involving deamidation of l-glutamine to l-glutamate followed by a transaminase (or dehydrogenase) reaction. However, mammalian tissues possess another pathway for conversion of l-glutamine to α-ketoglutarate, namely the glutaminase II pathway: l-Glutamine is transaminated to α-ketoglutaramate, which is then deamidated to α-ketoglutarate by ω-amidase.

NRH:quinone oxidoreductase 2 (NQO2) and glutaminase (GLS) both play a role in large extracellular vesicles (LEV) formation in preclinical LNCaP-C4-2B prostate cancer model of progressive metastasis.

In the course of studies aimed at the role of oxidative stress in the development of metastatic potential in the LNCaP-C4-2B prostate cancer progression model system, we found a relative decrease in the level of expression of the cytoplasmic nicotinamide riboside: quinone oxidoreductase (NQO2) and an increase in the oxidative stress in C4-2B cells compared to that in LNCaP or its derivatives C4 and C4-2. It was also found that C4-2B cells specifically shed large extracellular vesicles (LEVs) suggesting that these LEVs and their cargo could participate in the establishment of the osseous metastases. The level of expression of caveolin-1 increased as the system progresses from LNCaP to C4-2B.

ω-Amidase: an underappreciated, but important enzyme in L-glutamine and L-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases.

In mammals, two major routes exist for the metabolic conversion of L-glutamine to α-ketoglutarate. The most widely studied pathway involves the hydrolysis of L-glutamine to L-glutamate catalyzed by glutaminases, followed by the conversion of L-glutamate to α-ketoglutarate by the action of an L-glutamate-linked aminotransferase or via the glutamate dehydrogenase reaction. However, another major pathway exists in mammals for the conversion of L-glutamine to α-ketoglutarate (the glutaminase II pathway) in which L-glutamine is first transaminated to α-ketoglutaramate (KGM) followed by hydrolysis of KGM to α-ketoglutarate and ammonia catalyzed by an amidase known as ω-amidase.

Kynurenine aminotransferase III and glutamine transaminase L are identical enzymes that have cysteine S-conjugate β-lyase activity and can transaminate L-selenomethionine.

Three of the four kynurenine aminotransferases (KAT I, II, and IV) that synthesize kynurenic acid, a neuromodulator, are identical to glutamine transaminase K (GTK), α-aminoadipate aminotransferase, and mitochondrial aspartate aminotransferase, respectively. GTK/KAT I and aspartate aminotransferase/KAT IV possess cysteine S-conjugate β-lyase activity. The gene for the former enzyme, GTK/KAT I, is listed in mammalian genome data banks as CCBL1 (cysteine conjugate beta-lyase 1).

Curcumin Inhibits Prostate Cancer Bone Metastasis by Up-Regulating Bone Morphogenic Protein-7 .

A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy.

The administration of renoprotective agents extends warm ischemia in a rat model.

Background And Purpose: Extended warm ischemia time during partial nephrectomy leads to considerable renal injury. Using a rat model of renal ischemia, we examined the ability of a unique renoprotective cocktail to ameliorate warm ischemia-reperfusion injury and extend warm ischemia time.

Materials And Methods: A warm renal ischemia model was developed using Sprague-Dawley rats, clamping the left renal artery for 40, 50, 60, and 70 minutes, followed by 48 hours of reperfusion.

Amelioration of renal ischemia-reperfusion injury with a novel protective cocktail.

Purpose: Extended warm ischemia during partial nephrectomy can lead to considerable renal injury. Using a rat model of renal ischemia we examined the ability of a unique renoprotective cocktail to ameliorate warm ischemia-reperfusion injury.

Materials And Methods: A warm renal ischemia model was developed using 60 Sprague-Dawley® rats.

Right heterotaxy with Hirschsprung's disease - a new association.

A baby girl with prenatal diagnosis of complex cardiac anomalies and diaphragmatic hernia was born at 36 weeks of gestation. At 4 hr of life, the baby developed respiratory distress and was intubated. She was found to have right hetetrotaxy with total anomalous pulmonary venous drainage into the portal vein, five hepatic veins draining the liver and intrathoracic herniation of the stomach.

Hypoxic pre-conditioning in a rat renal ischemia model: an evaluation of the use of hydralazine.

Introduction: With the advent of improved diagnostic and imaging techniques, it is now possible to detect renal cancers in their very early stages, when they are still present as small renal masses. In these situations, use of laparoscopic partial nephrectomy (LPN) techniques are indicated and have gained acceptance in major medical institutions worldwide, offering comparable oncological outcomes and improving quality of life in the patient when contrasted with open nephrectomy procedures. However, a complication that may occur during or after this surgery is the possibility of compromising renal function, as a result of extended ischemia times of more than 30 min.

Role of carbonic anhydrases in the progression of renal cell carcinoma subtypes: proposal of a unified hypothesis.

Renal cell carcinoma (RCC) has the highest rate of occurrence within the US when compared with other countries. Recent advances in the basic research and molecular diagnostics of this malignancy have revealed that RCC is not a single disease, but it is a mixture of several types of malignancies with unique molecular mechanisms and pathological attributes. RCC is now divided into clear cell carcinoma (80% of all kidney cancers), papillary type 1 and papillary type 2 neoplasms (10-15% of all RCC patients) and RCC with chromophobic and oncocytic features, called the Birt-Hogg-Dube (BHD) subtype, in roughly 5% of all patients.

Solitary vascular malformation of the clitoris.

Isolated involvement of the clitoris by vascular malformation (VM) is very rare. Clinically, the lesion simulates female pseudohermaphroditism. A five-year-old girl presented with clitoromegaly and a clinical diagnosis of solitary VM of the clitoris was made.

The role of carbonic anhydrase IX overexpression in kidney cancer.

Carbonic anhydrase IX (CA IX) is a membrane isoenzyme, the overexpression of which is associated with clear cell carcinoma of the kidney. Its overexpression is restricted mainly to cancer, as it is absent in corresponding normal tissues making it a potential cancer biomarker. Several recent studies have shown that CA IX, apart from its classical enzyme activity of reversibly hydrating carbon dioxide extracellularly to facilitate the net extrusion of protons from inside to outside the cell, it can also be a key player in the modulation of cell adhesion processes and participate in the regulation of cell proliferation in response to hypoxic environment to ultimately contribute to tumour progression.

A case of supercarbia following pneumoperitoneum in an infant.

A 4-month-old healthy male infant underwent left herniotomy under general anesthesia with caudal block. Carbon dioxide (CO2) pneumoperitoneum was created through the left hernial sac for inspection of the right processus vaginalis. Episodes of desaturation associated with significant reduction in chest compliance were noted intraoperatively.

Role of chemopreventive agents in cancer therapy.

Tumorigenesis or carcinogenesis is a multi-step process that is induced primarily by carcinogens leading to the development of cancer. Extensive research in the last few years has revealed that regular consumption of certain fruits and vegetables can reduce the risk of acquiring specific cancers. Phytochemicals derived from such fruits and vegetables, referred to as chemopreventive agents include genistein, resveratrol, diallyl sulfide, S-allyl cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, silymarin, anethol, catechins and eugenol.

Clonal isolation of different strains of mouse mammary tumor virus-like DNA sequences from both the breast tumors and non-Hodgkin's lymphomas of individual patients diagnosed with both malignancies.

Purpose: In a previous study, we had detected the presence of mouse mammary tumor virus (MMTV)-like envelope (ENV) gene sequences in both the breast tumors and non-Hodgkin's lymphoma tissue of two of our breast tumor patients who had been diagnosed simultaneously with both malignancies. The aim of this study was to determine if MMTV-like DNA sequences are present in the breast tumors and non-Hodgkin's lymphomas of additional patients suffering from both malignancies and if so to characterize these sequences in detail.

Experimental Design: DNA was extracted from formalin-fixed, paraffin-embedded tissue sample blocks of breast tumors and non-Hodgkin's lymphomas from patients suffering from both malignancies.

Therapeutic potential of curcumin in prostate cancer--V: Interference with the osteomimetic properties of hormone refractory C4-2B prostate cancer cells.

Background: There is increasing evidence that the stringent selective pressure imposed by androgen ablation therapy on the residual prostate cancer cells may actually accelerate the development of the hormone refractory and bone metastatic phenotype. The propensity of prostate cancer to establish osseous metastases is very likely mediated by the osteomimetic properties of the prostate cancer cells. Prostate cancer cells acquire these "bone-like" properties in order to survive in the bony microenvironment.

Spermatic cord metastasis from a medulloblastoma.

A 4-year-old boy presented with metastases in the spermatic cord and ribs 2 years after treatment for a primary medulloblastoma (MB). The testis was free of tumor. A MB presenting with a metastasis to the spermatic cord has not been reported to date.

Umbilical evagination of the bladder with omphalocele minor.

A neonate with umbilical evagination of the bladder (UEB) and omphalocele minor (OM) is reported. The findings in this case support the origin of the urachus from the upper end of the cloaca rather than the allantois. The frequent occurrence of OM with urachal anomalies, including UEB, suggests an embryological association between the two conditions.

Mediastinal teratoma in a neonate.

A neonate with severe respiratory distress due to a benign mediastinal teratoma (MT) is reported. Despite early and easy surgical excision of the tumor, the child died due to poor cardiac function. Only ten cases of MT in neonates have been reported in the literature so far.