phosphocreatine and Cell-Transformation--Neoplastic

How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Creatine Kinase; Creatinine; Drug Resistance, Neoplasm; Energy Metabolism; Energy Transfer; Female; Gene Knockdown Techniques; Humans; Lapatinib; Mice; Mice, Nude; Mitochondria; Mitochondrial Proteins; Phosphocreatine; Phosphorylation; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

In vertebrates, phosphocreatine and ATP are continuously interconverted by the reversible reaction of creatine kinase in accordance with cellular energy needs. Sarcoma tissue and its normal counterpart, creatine-rich skeletal muscle, are good source materials to study the status of creatine and creatine kinase with the progression of malignancy. We experimentally induced sarcoma in mouse leg muscle by injecting either 3-methylcholanthrene or live sarcoma 180 cells into one hind leg. Creatine, phosphocreatine and creatine kinase isoform levels decreased as malignancy progressed and reached very low levels in the final stage of sarcoma development; all these parameters remained unaltered in the unaffected contralateral leg muscle of the same animal. Creatine and creatine kinase levels were also reduced significantly in frank malignant portions of human sarcoma and gastric and colonic adenocarcinoma compared with the distal nonmalignant portions of the same samples. In mice, immunoblotting with antibodies against cytosolic muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase showed that both of these isoforms decreased as malignancy progressed. Expressions of mRNA of muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase were also severely downregulated. In human sarcoma these two isoforms were undetectable also. In human gastric and colonic adenocarcinoma, brain-type creatine kinase was found to be downregulated, whereas ubiquitous mitochondrial creatine kinase was upregulated. These significantly decreased levels of creatine and creatine kinase isoforms in sarcoma suggest that: (a) the genuine muscle phenotype is lost during sarcoma progression, and (b) these parameters may be used as diagnostic marker and prognostic indicator of malignancy in this tissue.

Topics: Adenocarcinoma; Animals; Cell Transformation, Neoplastic; Colorectal Neoplasms; Creatine; Creatine Kinase; Creatine Kinase, BB Form; Creatine Kinase, Mitochondrial Form; Creatine Kinase, MM Form; Disease Progression; Humans; Immunoblotting; Mice; Muscle, Skeletal; Neoplasms, Muscle Tissue; Phosphocreatine; RNA, Messenger; Sarcoma; Sarcoma, Experimental; Stomach Neoplasms

Controversy exists about correlations between histological tumor grade and magnetic resonance (MR) spectroscopy data. The authors studied single-voxel proton MR spectroscopy as a noninvasive way to evaluate grade of malignancy in intracranial meningiomas.. The authors compared the results of MR spectroscopy with those derived by the MIB-1 staining index (SI) in 29 meningiomas. Proton MR spectroscopy was performed using stimulated echo acquisition and volume-localized solvent-attenuated proton nuclear MR sequences before surgery or other therapy. Twenty-four tumors were histologically benign (13 meningothelial, three fibrous, four transitional, three angiomatous, and one chordoid); four were atypical (Grade II), and one was papillary (Grade III). The mean MIB-1 SI in the benign group was significantly lower than those in the other groups (p = 0.0041). The mean choline-containing compound (Cho)/ creatine and phosphocreatine (Cr) ratios in the benign and nonbenign groups were 2.56+/-1.26 and 7.85+/-3.23, respectively (p = 0.0002). A significant linear correlation was observed between the Cho/Cr ratio and the MIB-1 SI (r0.05 = 0.74, p<0.001). Necrosis was present histologically in four of the five meningiomas classified either as atypical or papillary. Magnetic resonance spectroscopy revealed a methylene signal in these meningiomas that was not detected in benign meningiomas. Of the five meningiomas in which only a lactate signal was observed, two were benign and the MIB-1 SI in these two benign meningiomas was higher than the mean value for the benign group. Alanine, detected in 12 of 30 meningiomas, did not correlate with either tumor grade or Cho/Cr ratio.. Proton MR spectroscopy is a useful diagnostic method for determining the proliferative or malignant potential of meningiomas according to the Cho/Cr ratio. A lactate and/or methylene signal suggests a high-grade tumor.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Nuclear; Biomarkers, Tumor; Brain; Cell Division; Cell Transformation, Neoplastic; Choline; Creatine; Diagnosis, Differential; Energy Metabolism; Female; Humans; Hydrocarbons; Ki-67 Antigen; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Meningeal Neoplasms; Meninges; Meningioma; Methane; Middle Aged; Necrosis; Neoplasm Recurrence, Local; Nuclear Proteins; Phosphocreatine; Prognosis; Reoperation

The authors tested the hypothesis that proton magnetic resonance spectroscopy (1H-MRS) imaging can be used as a supportive diagnostic tool to differentiate clinically stable brain tumors from those progressing as a result of low- to high-grade malignant transformation or posttherapeutic recurrence. Twenty-seven patients with cerebral gliomas verified on histological examination were studied repeatedly with 1H-MRS imaging over a period of 3.5 years. At the time of each 1H-MRS imaging study, clinical examination, MR imaging, positron emission tomography with 18F-fluorodeoxyglucose, and biopsy findings (when available) were used to categorize each patient as having either stable or progressive disease. Measures of the percentage changes in the choline (Cho) 1H-MRS imaging signal intensity between studies, which were obtained without knowledge of the clinical categorization, allowed the investigators to segregate the groups with a high degree of statistical significance. All progressive cases showed a Cho signal increase between studies of more than 45%, whereas all stable cases showed an elevation of less than 35%, no change, or even a decreased signal. The authors conclude that increased Cho levels coincide with malignant degeneration of cerebral gliomas and therefore may possibly be used as a supportive indicator of progression of these neoplasms.

Topics: Adult; Aged; Aspartic Acid; Biomarkers, Tumor; Biopsy; Brain Neoplasms; Cell Transformation, Neoplastic; Choline; Creatine; Deoxyglucose; Disease Progression; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Follow-Up Studies; Glioma; Humans; Hydrogen; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neoplasm Recurrence, Local; Phosphocreatine; Prognosis; Protons; Radiopharmaceuticals; Tomography, Emission-Computed

In an effort to investigate the role of creatine kinase and its substrates in malignancy we have tested the effect of cyclocreatine [1-carboxymethyl-2-iminoimidazolidine (CCr)] on the growth of tumor cells in vitro and in vivo. CCr is phosphorylated by creatine kinase to yield a synthetic phosphagen [(N-phosphorylcyclocreatine (CCr approximately P)] with thermodynamic and kinetic properties distinct from those of creatine phosphate. We show that CCr accumulates as CCr approximately P in tumor cells expressing a high level of creatine kinase, and that the accumulation of this phosphagen is detrimental to tumor cell growth. Tumor cell lines expressing a low level of creatine kinase accumulate much less CCr approximately P, and consequently are growth inhibited only at higher concentrations of CCr. When these resistant cells are transfected with a creatine kinase B expression vector, they express creatine kinase, accumulate CCr approximately P, and are growth inhibited. In vivo, in nude mouse xenografts, the rate of growth of a high creatine kinase expressing tumor cell line is inhibited in animals fed 1% CCr. Our results indicate that CCr inhibits the growth of tumor cells in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Cell Division; Cell Line; Cell Transformation, Neoplastic; Creatine Kinase; Creatinine; Female; Humans; Imidazolidines; Isoenzymes; Male; Mice; Mice, Nude; Neoplasms; Neoplasms, Experimental; Phosphocreatine; Transplantation, Heterologous; Tumor Cells, Cultured; Uterine Cervical Neoplasms