Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death

Steták, Attila; Veress, Réka; Ovádi, Judit; Csermely, Péter; Kéri, Gÿorgý; Ullrich, Axel

doi:10.1158/0008-5472.can-06-2870

Cited by 167 publications

(136 citation statements)

References 28 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…It has been proven that the downregulation of PKM2 activity in cancer cells aids in shunting key glycolytic intermediates toward pathways where they, in turn, are utilized as precursors for lipid, amino acid and nucleic acid synthesis. Therefore, the downregulation of PKM2 activity provides a purposeful divergence from catabolic metabolism aimed at energy production toward an anabolic state aimed at providing the needed resources for rapid cellular construction (33). Research has also shown that PKM2 plays a general role in caspase-and Bcl-independent apoptosis, thereby validating PKM2 as a promising, generally relevant target for the development of anticancer therapies with broad efficacy (34).…”

Section: Discussionmentioning

confidence: 99%

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat

Huang

Tang

Zhou

et al. 2012

International Journal of Oncology

View full text Add to dashboard Cite

Abstract.Orlistat is an orally administered anti-obesity drug that has shown significant antitumor activity in a variety of tumor cells. To identify the proteins involved in its antitumor activity, we employed a proteomic approach to reveal protein expression changes in the human ovarian cancer cell line SKOV3, following Orlistat treatment. Protein expression profiles were analyzed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument. More than 110 differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue staining. Furthermore, 71 proteins differentially expressed proteins were positively identified via mass spectrometry (MS)/MS analysis. In particular, PKM1/2, a key enzyme involved in tumorigenesis, was found to be significantly downregulated in SKOV3 cells following treatment with Orlistat. Moreover, PKM1/2 was proved to be downregulated in SKOV3 cells by western blot analysis after treatment with Orlistat. Taken together, using proteomic tools, we identified several differentially expressed proteins that underwent Orlistat-induced apoptosis, particularly PKM2. These changes confirmed our hypothesis that Orlistat is a potential inhibitor of ovarian cancer and can be used as a novel adjuvant antitumor agent. IntroductionIn the 1920s, the Nobel Prize winner Otto Warburg observed a marked increase in glycolysis and enhanced lactate production in tumor cells even when maintained in conditions of high oxygen tension (termed Warburg effect), leading to widespread concerns about the metabolic changes in human types of cancer (1). Either as a consequence or as a cause, alterations of cancer cell-intrinsic metabolism have been considered as essential hallmarks of cancer. Among these metabolic changes, de novo fatty acid biosynthesis was found elevated in the majority of human types of cancer, such as prostate (2), colorectal (3), ovarian (4), bladder (5), esophageal (6), gastric (7), lung (8), endometrial (9), breast (10) and soft tissue sarcomas (11). Fatty acid synthase (FASN) is regarded as a key regulator of de novo fatty acid synthesis and was widely found upregulated in a wide variety of human malignancies and their pre-neoplastic lesions. Recent studies also reveal that FASN is associated with the stage of cancer and indicate a poor prognosis (12). Thus, FASN could be considered as a reliable predictor of recurrence and disease-free survival along with neo-plastic stage (13). In vivo treatment with inhibitors of FASN has been proven to lead to markedly decreased survival in human cancer xenografts (14) and silencing of the FASN gene by siRNA also inhibits cancer cell growth and ultimately induces cancer cell apoptosis (15). Therefore, agents that inhibit FASN and the de novo fatty-acid synthesis pathways could be considered as novel antitumor strategies.Orlistat, an anti-obesity drug approved by the US Food and Drug Administration, which possesses extremely low oral bio-availability (16), exhibits anti-p...

show abstract

Section: Discussionmentioning

confidence: 99%

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat

Huang

Tang

Zhou

et al. 2012

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…A variety of molecules interact with PKM2 (5,6,8,14,18,19,21,23,24,28,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Many of them affect the glycolytic functions of PKM2, which directly regulate the Warburg effect.…”

Section: Nonglycolytic Functions Of Pkm2mentioning

confidence: 99%

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

204

199

View full text Add to dashboard Cite

The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.

show abstract

“…Recently, it was shown that somatostatin and its structural analogue induces nuclear translocation of M2-PK [88]. Nuclear translocation of M2-PK induced programmed cell death in Cos-7 cells.…”

Section: Il-3-induced Nuclear Translocation Of Pyruvate Kinasementioning

confidence: 99%

Cytokine-induced nuclear translocation of signaling proteins and their analysis using the inducible translocation trap system

Fleur

Fujii

2008

Cytokine

View full text Add to dashboard Cite

Binding of cytokines to their specific receptors induces activation of signal transduction pathways, many of which involve nuclear translocation of signaling proteins. In this review, an overview of cytokine-induced nuclear translocation of signaling proteins is provided. In addition, inducible translocation trap (ITT), a novel reporter-based system to detect nuclear translocation, and its application for identification of nuclear translocating proteins are elaborated. Finally, analysis of "nuclear translocatome", the entire set of proteins that translocate into or out of the nucleus in response to extracellular stimuli, by ITT is discussed.

show abstract

Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death

Cited by 167 publications

References 28 publications

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat

Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Cytokine-induced nuclear translocation of signaling proteins and their analysis using the inducible translocation trap system

Contact Info

Product

Resources

About