Expression of Two Type II-Like Tumor Hexokinase RNA Transcripts in Cancer Cell Lines

Sebastian, Siby; Kenkare, Umakant W.

doi:10.1159/000030015

Cited by 18 publications

(11 citation statements)

References 27 publications

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“…An elevated glycolysis rate and the expression of the glycolytic enzymes such as hexokinases in pancreatic tumors has been observed (49), which is consistently confirmed by PET imaging in pancreatic cancer patients (50,51). These characteristics are also associated with increased metastasis and poor survival rates in cancer patients (18).…”

Section: Discussionmentioning

confidence: 84%

Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor

Cao

Bloomston²,

Zhang³

et al. 2008

Clinical Cancer Research

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Purpose: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production. Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging. Results: Hypoxia enhanced HIF-1aexpression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven-to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17-to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition. Conclusions:The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapyresistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.

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Section: Discussionmentioning

confidence: 84%

Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor

Cao

Bloomston²,

Zhang³

et al. 2008

Clinical Cancer Research

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“…1978; Verhagen et al . 1985; Sebastian and Kenkare 1998; for a review see Mathupala et al . 1997; Pedersen et al .…”

Section: Discussionmentioning

confidence: 99%

Endothelin‐1 stimulates the translocation and upregulation of both glucose transporter and hexokinase in astrocytes: relationship with gap junctional communication

Sánchez‐Alvarez

Tabernero

Medina

2004

Journal of Neurochemistry

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We have previously shown that endothelin-1 increases glucose uptake in astrocytes. In the present work we investigate the mechanism through which endothelin-1 (ET-1) increases glucose uptake. Our results show that ET-1 activates a short-term and a long-term mechanism. Thus, ET-1 induced a rapid change in the localization of both GLUT-1 and type I hexokinase. These changes are probably aimed at rapidly increasing the entry and phosphorylation of glucose. In addition, ET-1 upregulated GLUT-1 and type I hexokinase and induced the expression of isoforms not normally expressed in astrocytes, such as GLUT-3 and type II hexokinase. These changes provide astrocytes with the machinery required to sustain a high rate of glucose uptake for a longer period of time. Our previous work had suggested that the effect of ET-1 on glucose uptake was associated with the inhibition of gap junctions. In this work, we compare the effect of ET-1 with that of carbenoxolone, a classical inhibitor of gap junction communication. Carbenoxolone increased glucose uptake to the same extent as ET-1 following the same mechanisms. Thus, carbenoxolone induced a rapid change in the localization of both GLUT-1 and type I hexokinase, upregulated GLUT-1 and type I hexokinase and induced the expression of GLUT-3 and type II hexokinase. When the inhibition of gap junction was prevented by tolbutamide, neither ET-1 nor carbenoxolone were able to increase the levels of GLUT-1, GLUT-3, type I hexokinase or type II hexokinase, indicating that these events are closely related to gap junctions.

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“…Cancer-associated alterations in the expression level of PTPC components have been described for ANT (206), HK (640,693), the peripheral-type benzodiazepine receptor (PBR) (472), and VDAC (715). PTPC proteins may be overexpressed in various tumors and cancer cell lines (707).…”

Section: E Cancermentioning

confidence: 99%

Mitochondrial Membrane Permeabilization in Cell Death

Kroemer¹,

Galluzzi²,

Brenner³

2007

Physiological Reviews

3,189

2,742

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Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

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Expression of Two Type II-Like Tumor Hexokinase RNA Transcripts in Cancer Cell Lines

Cited by 18 publications

References 27 publications

Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor

Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor

Endothelin‐1 stimulates the translocation and upregulation of both glucose transporter and hexokinase in astrocytes: relationship with gap junctional communication

Mitochondrial Membrane Permeabilization in Cell Death

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