Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells

Tamada, Mayumi; Nagano, Osamu; Tateyama, Seiji; Ohmura, Mitsuyo; Yae, Toshifumi; Ishimoto, Takatsugu; Sugihara, Eiji; Onishi, Nobuyuki; Yamamoto, Takehiro; Yanagawa, Hiroshi; Suematsu, Makoto; Saya, Hideyuki

doi:10.1158/0008-5472.can-11-3024

Cited by 222 publications

(213 citation statements)

References 42 publications

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“…While CD44-HA interaction is one important factor (33), a shift toward CD44v in epithelial-mesenchymal transition (34), hepatocellular carcinoma (HCC) (35), squamous cell carcinoma (36), a role of CD44v6 in preparation of the metastatic niche (37), or CD44-mediated drug resistance (38)(39)(40) in ovarian cancer (41) were reported.…”

Section: Discussionmentioning

confidence: 99%

CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients

Birzele¹,

Voß²,

Nopora³

et al. 2015

Clinical Cancer Research

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Purpose: CD44, a cell surface glycoprotein, plays important roles in the development, progression, and metastasis of various tumor types. The aim of this study was to investigate how the expression of CD44 isoforms influences the interaction with hyaluronic acid (HA) and how differential isoform expression impacts antitumoral responses in vivo to treatment with RG7356, a humanized anti-CD44 antibody inhibiting CD44-HA interaction.Experimental Design: CD44 isoform expression on various tumor cell lines was analyzed by RNASeq while data on patients with different tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study (NCT01358903). We analyzed the link between HA production and CD44 isoform expression as well as the consequences of blocking the CD44-mediated cell adhesion to HA using RG7356.The correlation between CD44 isoform expression and antitumor response to RG7356 treatment was investigated in the corresponding murine xenograft in vivo models as well as in a subset of patients treated with RG7356 from a recently completed phase I clinical trial.Results: CD44 isoform expression, in particular expression of CD44s, is associated with HA production and predicts response to treatment with RG7356 in tumor xenograft models. Furthermore, patient data suggest that CD44 isoform status is a potential predictive biomarker for clinical response to treatment with RG7356.Conclusions: We provide new insights into the close interplay between CD44 and HA and a potential biomarker to enrich patient responses to RG7356 in the clinic.

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Section: Discussionmentioning

confidence: 99%

CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients

Birzele¹,

Voß²,

Nopora³

et al. 2015

Clinical Cancer Research

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“…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

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207

199

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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.

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“…61,62 While the ratio of reduced glutathione (GSH), the primary intracellular antioxidant, to oxidized (GSSH) glutathione decreases, as does the level of NADH, during stem cell differentiation, CSC possess enhanced mechanisms of protection from stress induced by ROS that might render them resistant to chemo-and radiotherapy through an upregulation of GSH synthesis. [76][77][78] Consequently, new strategies aimed to induce ROS via depletion of cellular glutathione can be viewed as promising therapeutic approaches against CSC. [79][80][81] Third lesson: Metabolism of amino acids and fatty acids…”

Section: Metabolism and Cancer Stemness: Lessons From Ips Cellsmentioning

confidence: 99%

Metabolic control of cancer cell stemness: Lessons from iPS cells

Menendez

2015

Cell Cycle

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Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells

Cited by 222 publications

References 42 publications

CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients

CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients

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

Metabolic control of cancer cell stemness: Lessons from iPS cells

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