Mitochondrial creatine kinase in cancer patients

Pratt, Robin; Vallis, Lea M.; Lim, Chew W.; Chisnall, Wayne N.

doi:10.3109/00313028709077128

Cited by 32 publications

(31 citation statements)

References 11 publications

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“…In fact, CK is overexpressed in most tumors as compared to the corresponding non-malignant tissue. 6,8,33 Downregulation of B-CK in breast cancer correlates with growth inhibition 34 and elevated CK plasma levels are a diagnostic marker 35 correlating with aggressiveness of cancer cells. 36 Overexpression of mitochondrial CK was also described as a marker for poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…9 Elevated levels of CK have been detected in the sera of patients with advanced-stage cancer and are characteristic for a poor prognosis. 6,8,10 CK catalyzes the reversible transphosphorylation between ATP and creatine: creatine ϩ ATP 7 phosphocreatine ϩ ADP.The enzyme is thought to have 2 main functions in energy metabolism. 4 It buffers the cellular ATP pool by maintaining high cytosolic concentrations of phosphocreatine (PCr), which can be used in times of high cellular energy demand for the regeneration of ATP and it maintains an energy shuttle between subcellular sites of energy supply (oxidative phosphorylation, glycolysis) and sites of energy demand using the easily diffusable Cr/PCr.…”

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confidence: 99%

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confidence: 99%

“…The cytosolic braintype isoform (B-CK) is coexpressed with the ubiquitous mitochondrial isoform (uMtCK) in many cells and tissues with a high energy demand like brain, placenta, kidney, testis, sperm or endothelial cells. 4 Overexpression of CK has been demonstrated in a wide variety of solid tumors [5][6][7][8] and tumor cell lines. 9 Elevated levels of CK have been detected in the sera of patients with advanced-stage cancer and are characteristic for a poor prognosis.…”

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Hodgkin disease‐derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis

Kornacker

Schlattner²,

Wallimann³

et al. 2001

Int. J. Cancer

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Ubiquitous mitochondrial creatine kinase (uMtCK), a key enzyme in energy metabolism, was identified by differential display PCR to be specifically overexpressed in L1236, the first cell line of definite Hodgkin origin. RT-PCR confirmed overexpression of uMtCK in the L1236 cell line and the absence of cytosolic B-CK, which is co-expressed with MtCK physiologically. Cyclocreatine (cCr), whose phosphorylated form is a very poor substrate for CK, inhibited proliferation of the L1236 cell line nearly entirely. This inhibition by cCr was partially reversed by competition with creatine, which by itself had no effect on proliferation of the L1236 cell line. In Hodgkin disease (HD), the telltale Hodgkin and Reed-Sternberg (H-RS) cells are surrounded by reactive tissue components. The scarcity of the malignant cells has hampered their genetic analysis. Only recently, single cell PCR analysis could show a clonal B-cell origin of the H-RS cells. 1 Sequence analysis demonstrated that these cells lost their immunoglobulin (Ig) expression due to crippling mutations acquired in the germinal centre. Normal B-cells unable to express Ig are prevented from antigenic selection and are eliminated by apoptosis. The transforming event in HD allowing the cells to escape from programmed cell death is not known. One possible candidate is Epstein-Barr virus (EBV), which is found in 50% of HD cases and has been shown to upregulate the antiapoptotic gene bcl-2 in infected cells. 2 In addition, the complex chromosomal aberrations seen in HD 3 may cause changes in gene expression resulting in resistance to apoptosis. Because of the considerable karyotypic variation from case to case, different molecular mechanisms may be involved in malignant transformation in HD and, in support of this, no HD specific genetic aberration could be identified so far.One of the mechanisms possibly involved in malignant transformation is overexpression of creatine kinase (CK). The enzyme reversibly catalyzes the transfer of a phosphate group from ATP to creatine (Cr) and occurs as different isoforms. The cytosolic braintype isoform (B-CK) is coexpressed with the ubiquitous mitochondrial isoform (uMtCK) in many cells and tissues with a high energy demand like brain, placenta, kidney, testis, sperm or endothelial cells. 4 Overexpression of CK has been demonstrated in a wide variety of solid tumors 5-8 and tumor cell lines. 9 Elevated levels of CK have been detected in the sera of patients with advanced-stage cancer and are characteristic for a poor prognosis. 6,8,10 CK catalyzes the reversible transphosphorylation between ATP and creatine: creatine ϩ ATP 7 phosphocreatine ϩ ADP.The enzyme is thought to have 2 main functions in energy metabolism. 4 It buffers the cellular ATP pool by maintaining high cytosolic concentrations of phosphocreatine (PCr), which can be used in times of high cellular energy demand for the regeneration of ATP and it maintains an energy shuttle between subcellular sites of energy supply (oxidative phosphorylation, glycolysis) and sites of ene...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Hodgkin disease‐derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis

Kornacker

Schlattner²,

Wallimann³

et al. 2001

Int. J. Cancer

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“…This intimate exchange of substrates and products, the so-called functional coupling or metabolite channeling (10,11), fulfills important functions that may vary among different tissues, species, and developmental states (12,13): (i) phosphocreatine becomes the high energy intermediate that is exported from mitochondria into the cytosol (3); (ii) locally generated ADP stimulates oxidative phosphorylation (11); and (iii) ADP channeled through the MtCK/ANT interaction inhibits the Ca 2ϩ -induced opening of the mitochondrial permeability transition pore (14,15), a well known trigger of apoptosis (16,17). Thus, overexpression of uMtCK in many malignant cancers with especially poor prognosis (18,19) may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. MtCK functions in energy buffering and transport, as well as permeability transition pore regulation may also explain the supportive and protective effects of the CK substrate creatine in many muscular, neurodegenerative, and age-related disorders (20 -22).…”

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C-terminal Lysines Determine Phospholipid Interaction of Sarcomeric Mitochondrial Creatine Kinase

Schlattner

Gehring

Vernoux

et al. 2004

Journal of Biological Chemistry

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High affinity interaction between octameric mitochondrial creatine kinase (MtCK) and the phospholipid cardiolipin in the inner mitochondrial membrane plays an important role in metabolite channeling between MtCK and inner membrane adenylate translocator, which itself is tightly bound to cardiolipin. Three Cterminal basic residues revealed as putative cardiolipin anchors in the x-ray structures of MtCK and corresponding to lysines in human sarcomeric MtCK (sMtCK) were exchanged by in vitro mutagenesis (K369A/E, K379Q/A/E, K380Q/A/E) to yield double and triple mutants. sMtCK proteins were bacterially expressed, purified to homogeneity, and verified for structural integrity by enzymatic activity, gel filtration chromatography, and CD spectroscopy. Interaction with cardiolipin and other acidic phospholipids was quantitatively analyzed by light scattering, surface plasmon resonance, and fluorescence spectroscopy. All mutant sMtCKs showed a strong decrease in vesicle cross-linking, membrane affinity, binding capacity, membrane ordering capability, and binding-induced changes in protein structure as compared with wild type. These effects did not depend on the nature of the replacing amino acid but on the number of exchanged lysines. They were moderate for Lys-379/Lys-380 double mutants but pronounced for triple mutants, with a 30-fold lower membrane affinity and an entire lack of alterations in protein structure compared with wild-type sMtCK. However, even triple mutants partially maintained an increased order of cardiolipin-containing membranes. Thus, the three Cterminal lysines determine high affinity sMtCK/cardiolipin interaction and its effects on MtCK structure, whereas low level binding and some effect on membrane fluidity depend on other structural components. These results are discussed in regard to MtCK microcompartments and evolution.

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Crystal structure of human ubiquitous mitochondrial creatine kinase

et al. 2000

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Creatine kinase (CK), catalyzing the reversible trans-phosphorylation between ATP and creatine, plays a key role in the energy metabolism of cells with high and fluctuating energy requirements. We have solved the X-ray structure of octameric human ubiquitous mitochondrial CK (uMtCK) at 2.7 A resolution, representing the first human CK structure. The structure is very similar to the previously determined structure of sarcomeric mitochondrial CK (sMtCK). The cuboidal octamer has 422 point group symmetry with four dimers arranged along the fourfold axis and a central channel of approximately 20 A diameter, which extends through the whole octamer. Structural differences with respect to sMtCK are found in isoform-specific regions important for octamer formation and membrane binding. Octameric uMtCK is stabilized by numerous additional polar interactions between the N-termini of neighboring dimers, which extend into the central channel and form clamp-like structures, and by a pair of salt bridges in the hydrophobic interaction patch. The five C-terminal residues of uMtCK, carrying positive charges likely to be involved in phospholipid-binding, are poorly defined by electron density, indicating a more flexible region than the corresponding one in sMtCK. The structural differences between uMtCK and sMtCK are consistent with biochemical studies on octamer stability and membrane binding of the two isoforms.

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Mitochondrial creatine kinase in cancer patients

Cited by 32 publications

References 11 publications

Hodgkin disease‐derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis

Hodgkin disease‐derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis

C-terminal Lysines Determine Phospholipid Interaction of Sarcomeric Mitochondrial Creatine Kinase

Crystal structure of human ubiquitous mitochondrial creatine kinase

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