Nuclear Insulin-Like Growth Factor Binding Protein-3 Induces Apoptosis and Is Targeted to Ubiquitin/Proteasome–Dependent Proteolysis

Santer, Frédéric R.; Bacher, Nicole; Moser, Barbara; Morandell, Dieter; Ressler, Sigrun; Firth, Sue M.; Spoden, Gilles A.; Sergi, Consolato; Baxter, Robert C.; Jansen‐Dürr, Pidder; Zwerschke, Werner

doi:10.1158/0008-5472.can-05-2013

Cited by 67 publications

(57 citation statements)

References 40 publications

(48 reference statements)

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“…Apoptotic cells were detected according to Nicoletti et al 23 or by Annexin V staining 22 and counted by flow cytometry using a Becton Dickinson FACSCalibur and CellQuest software.…”

Section: Apoptosis Assaysmentioning

confidence: 99%

Isotype‐specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation

Spoden

Mazurek

Morandell

et al. 2008

Intl Journal of Cancer

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Tumor cells express the glycolytic regulator pyruvate kinase subtype M2 (M2-PK), which can occur in a tetrameric form with high affinity to its substrate phosphoenolpyruvate (PEP) and a dimeric form with a low PEP affinity. The transition between both conformations contributes to the control of glycolysis and is important for tumor cell proliferation and survival. Here we targeted M2-PK by synthetic peptide aptamers, which specifically bind to M2-PK and shift the isoenzyme into its low affinity dimeric conformation. The aptamer-induced dimerization and inactivation of M2-PK led to a significant decrease in the PK mass-action ratio as well as ATP:ADP ratio in the target cells. Furthermore, the expression of M2-PK-binding peptide aptamers moderately reduced the growth of immortalized NIH3T3 cell populations by decelerating cell proliferation, but without affecting apoptotic cell death. Moreover, the M2-PK-binding peptide aptamers also reduced the proliferation rate of human U-2 OS osteosarcoma cells. In the present study, we developed the first specific inhibitors of the pyruvate kinase isoenzyme type M2 and present evidence that these inhibitors moderately decelerate tumor cell proliferation. ' 2008 Wiley-Liss, Inc.Key words: tumor metabolism; peptide aptamer; proliferation; pyruvate kinase Tumorigenesis is characterized by an increase in glycolytic enzyme activities as well as distinct changes in the glycolytic isoenzyme equipment. 1-3 A key glycolytic enzyme which is consistently altered in tumor cells is pyruvate kinase (EC 2.7.1.40), catalyzing the dephosphorylation of phosphoenolpyruvate (PEP) to pyruvate, which significantly contributes to net adenosine triphosphate (ATP) production within the glycolytic pathway. Depending on the metabolic functions of various tissues, different isoenzymes of pyruvate kinase are expressed. 4 The pyruvate kinase isoenzyme M1 (M1-PK) is characteristic for tissues with high energy turnover (muscle and brain), whereas the pyruvate kinase isoform L (L-PK) is found in tissues with gluconeogenesis, such as liver. When quiescent cells re-enter the cell cycle, as during tumorigenesis, the tissue-specific isoenzymes disappear and the pyruvate kinase isoenzyme type M2 (M2-PK) is expressed. 3,4 According to the different metabolic functions, M1-PK has the highest affinity to its substrate PEP, whereas the PEP affinity of M2-PK depends on its quaternary structure. M2-PK occurs as a tetrameric form characterized by a high affinity to its substrate PEP which is highly active at physiological PEP concentrations and as a dimeric form with low PEP affinity which is nearly inactive under physiological conditions. 3 The tetrameric but not the dimeric form of M2-PK is associated with other glycolytic enzymes as well as with lactate dehydrogenase (LDH), nucleotide diphosphate kinase and adenylate kinase, within a large complex, referred to as the glycolytic enzyme complex. 5-7 A high amount of the tetrameric form of M2-PK correlates with a relative high PK mass-action ratio ([pyruvate] AE[ATP])...

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“…Apoptotic cells were detected according to Nicoletti et al 23 or by Annexin V staining 22 and counted by flow cytometry using a Becton Dickinson FACSCalibur and CellQuest software.…”

Section: Apoptosis Assaysmentioning

confidence: 99%

Isotype‐specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation

Spoden

Mazurek

Morandell

et al. 2008

Intl Journal of Cancer

Self Cite

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“…Most major IGFBPs have both IGFdependent and independent actions, the former exerted by binding and sequestering IGF and the latter by binding directly to cell membrane and nuclear receptors. IGFBP-3, in particular, displays antiproliferative effects and pro-apoptotic effects both through and independently of the p53 downstream pathway [Buckbinder et al 1995;Butt et al 2000;Devi et al 2000;Santer et al 2006;Kim et al 2004]. Levels of serum IGFBPs appear to be prognostic in NSCLC patients whether they are treated with an epidermal growth factor receptor (EGFR) tyrosine kinase receptor (TKI) drug or systemic chemotherapy [Fidler et al 2009;Karmali et al 2010].…”

Section: Introductionmentioning

confidence: 99%

Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls

et al. 2011

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The insulin-like growth factor pathway The insulin-like growth factor (IGF) Abstract: The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.

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“…Most recent studies have suggested that ubiquitinproteasome-dependent proteolysis is also involved in apoptosis, although its precise role is controversial (7). Inhibitors of the proteasome can act through multiple mechanisms to arrest tumor growth, tumor spreading and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Tartrate-resistant acid phosphatase as a diagnostic factor for arthritis

Seol

Lee²,

Kim³

et al. 2009

Int J Mol Med

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Abstract. Tartrate-resistant acid phosphatase (TRAP) is highly expressed in osteoclasts and chondroclasts. The present study investigated changes in TRAP activity after chondrocyte death and cartilage damage, and also evaluated the possible use of TRAP as a diagnostic factor in a model of osteoarthritis. We induced experimental osteoarthritis in beagle dogs and separated chondrocytes from articular cartilage using an enzyme probe. Chondrocyte death was induced by proteasome inhibition and TRAIL treatment, and levels of lactate dehydrogenase, reactive oxygen species (ROS), caspase activation and TRAP activity were measured in the chondrocytes and synovial fluid. Proteasome inhibition and TRAIL treatment significantly enhanced chondrocyte death via caspase-8 activation and ROS generation in the primary cultured canine chondrocytes. TRAP activity was highly increased in damaged chondrocytes, but was decreased by blocking chondrocyte death using caspase inhibition or an ROS scavenger. In the synovial fluid of osteoarthritic dogs, TRAP activity as well as caspase activation and ROS levels were higher than those in the normal joint. Our study demonstrated that TRAP is activated by apoptosis and oxidative stress in primary cultured chondrocytes and osteoarthritic joints and also suggests that TRAP may be used as a diagnostic biomarker for detection of cartilage-related diseases, including osteoarthritis.

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Nuclear Insulin-Like Growth Factor Binding Protein-3 Induces Apoptosis and Is Targeted to Ubiquitin/Proteasome–Dependent Proteolysis

Cited by 67 publications

References 40 publications

Isotype‐specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation

Isotype‐specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation

Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls

Tartrate-resistant acid phosphatase as a diagnostic factor for arthritis

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