Limits...
Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight.

Savaskan NE, Fan Z, Broggini T, Buchfelder M, Eyüpoglu IY - Curr Neuropharmacol (2015)

Bottom Line: Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis.Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage.Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Universitatsklinikum Erlangen, Friedrich Alexander University of Erlangen- Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany. nicolai.savaskan@uk-erlangen.de.

ABSTRACT
Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.

No MeSH data available.


Related in: MedlinePlus

The heterodimeric glutamate-cystine antiporter system Xc-/xCT (SCL7a11) and its relation to TRP channels. xCT is anintegral membrane protein with 12 transmembrane domains and forms a complex with CD98. xCT transports Na+-independent glutamate outin exchange for cystine. Cystine is further processed to its reduced form cysteine which is further acquired for protein and glutathione (GSH)biosynthesis. The ‘glutathione-only’ hypothesis defines this particular function essential for cancer cells. A competing concept sets glutamatein the focus of the biology of brain tumors (glutamate-microenvironment hypothesis). The glutamate-microenvironment hypothesis issupported by data demonstrating that xCT knock down or genetic xCT deficiency is not essential for cell growth. Further, TRP channels areROS-sensitive and can mediate glutamate release. In this scheme it is speculated that TRP channels may challenge xCT transporter activity.Abbreviations: Cys, cysteine; Glu, glutamate; GSH, glutathione; ROS, reactive oxygen species.
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Figure 1: The heterodimeric glutamate-cystine antiporter system Xc-/xCT (SCL7a11) and its relation to TRP channels. xCT is anintegral membrane protein with 12 transmembrane domains and forms a complex with CD98. xCT transports Na+-independent glutamate outin exchange for cystine. Cystine is further processed to its reduced form cysteine which is further acquired for protein and glutathione (GSH)biosynthesis. The ‘glutathione-only’ hypothesis defines this particular function essential for cancer cells. A competing concept sets glutamatein the focus of the biology of brain tumors (glutamate-microenvironment hypothesis). The glutamate-microenvironment hypothesis issupported by data demonstrating that xCT knock down or genetic xCT deficiency is not essential for cell growth. Further, TRP channels areROS-sensitive and can mediate glutamate release. In this scheme it is speculated that TRP channels may challenge xCT transporter activity.Abbreviations: Cys, cysteine; Glu, glutamate; GSH, glutathione; ROS, reactive oxygen species.

Mentions: There exist now ample evidence that the cystine/glutamate antiporter xCT is expressed in various malignant tumors such as leukemias [17, 18], lymphomas [19-21], Karposi´s sarcoma [21, 22], pancreatic cancer [23], breast cancer [24, 25], squamous cell carcinoma/epithelial carcinomas [26, 27] and brain tumors [5, 28, 29]. There, the cystine/glutamate antiporter system xc- is composed of the catalytic domain xCT (solute carrier family 7 member 11, SLC7a11) and its heavy chain chaperone CD98/4F2hc (SLC3A2) (Fig. 1). In this complex, xCT functions as a Na-independent electro-neutral exchange system for cystine/glutamate with cystine entry and glutamate efflux in a 1:1 molar ratio [30, 31]. Intracellular cystine becomes reduced to cysteine required for the tripeptide glutathione (GSH) and protein biosynthetic pathways (Fig. 1). Importantly, cysteine is the rate-limiting substrate for GSH synthesis and GSH is required for proliferation, redox cycling and antioxidative defense [32, 33]. This dual function of system xc- (xCT) and its interrelation to cell proliferation led to the concept of targeting xCT in cancer. The idea on which inhibition of xCT is based on was to reduce intracellular glutathione levels and thereby subsequently disturbing cellular redox balance leading eventually to cancer cell death. Such cytotoxic strategy is especially appealing when the drug target acts specifically on cancer cells and target inhibition does not awry normal cell functioning within the therapeutic window.


Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight.

Savaskan NE, Fan Z, Broggini T, Buchfelder M, Eyüpoglu IY - Curr Neuropharmacol (2015)

The heterodimeric glutamate-cystine antiporter system Xc-/xCT (SCL7a11) and its relation to TRP channels. xCT is anintegral membrane protein with 12 transmembrane domains and forms a complex with CD98. xCT transports Na+-independent glutamate outin exchange for cystine. Cystine is further processed to its reduced form cysteine which is further acquired for protein and glutathione (GSH)biosynthesis. The ‘glutathione-only’ hypothesis defines this particular function essential for cancer cells. A competing concept sets glutamatein the focus of the biology of brain tumors (glutamate-microenvironment hypothesis). The glutamate-microenvironment hypothesis issupported by data demonstrating that xCT knock down or genetic xCT deficiency is not essential for cell growth. Further, TRP channels areROS-sensitive and can mediate glutamate release. In this scheme it is speculated that TRP channels may challenge xCT transporter activity.Abbreviations: Cys, cysteine; Glu, glutamate; GSH, glutathione; ROS, reactive oxygen species.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4598438&req=5

Figure 1: The heterodimeric glutamate-cystine antiporter system Xc-/xCT (SCL7a11) and its relation to TRP channels. xCT is anintegral membrane protein with 12 transmembrane domains and forms a complex with CD98. xCT transports Na+-independent glutamate outin exchange for cystine. Cystine is further processed to its reduced form cysteine which is further acquired for protein and glutathione (GSH)biosynthesis. The ‘glutathione-only’ hypothesis defines this particular function essential for cancer cells. A competing concept sets glutamatein the focus of the biology of brain tumors (glutamate-microenvironment hypothesis). The glutamate-microenvironment hypothesis issupported by data demonstrating that xCT knock down or genetic xCT deficiency is not essential for cell growth. Further, TRP channels areROS-sensitive and can mediate glutamate release. In this scheme it is speculated that TRP channels may challenge xCT transporter activity.Abbreviations: Cys, cysteine; Glu, glutamate; GSH, glutathione; ROS, reactive oxygen species.
Mentions: There exist now ample evidence that the cystine/glutamate antiporter xCT is expressed in various malignant tumors such as leukemias [17, 18], lymphomas [19-21], Karposi´s sarcoma [21, 22], pancreatic cancer [23], breast cancer [24, 25], squamous cell carcinoma/epithelial carcinomas [26, 27] and brain tumors [5, 28, 29]. There, the cystine/glutamate antiporter system xc- is composed of the catalytic domain xCT (solute carrier family 7 member 11, SLC7a11) and its heavy chain chaperone CD98/4F2hc (SLC3A2) (Fig. 1). In this complex, xCT functions as a Na-independent electro-neutral exchange system for cystine/glutamate with cystine entry and glutamate efflux in a 1:1 molar ratio [30, 31]. Intracellular cystine becomes reduced to cysteine required for the tripeptide glutathione (GSH) and protein biosynthetic pathways (Fig. 1). Importantly, cysteine is the rate-limiting substrate for GSH synthesis and GSH is required for proliferation, redox cycling and antioxidative defense [32, 33]. This dual function of system xc- (xCT) and its interrelation to cell proliferation led to the concept of targeting xCT in cancer. The idea on which inhibition of xCT is based on was to reduce intracellular glutathione levels and thereby subsequently disturbing cellular redox balance leading eventually to cancer cell death. Such cytotoxic strategy is especially appealing when the drug target acts specifically on cancer cells and target inhibition does not awry normal cell functioning within the therapeutic window.

Bottom Line: Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis.Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage.Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Universitatsklinikum Erlangen, Friedrich Alexander University of Erlangen- Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany. nicolai.savaskan@uk-erlangen.de.

ABSTRACT
Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.

No MeSH data available.


Related in: MedlinePlus