Universität zu Köln

Wolf, Ines M. L., Fan, Zheng, Rauh, Manfred, Seufert, Sebastian, Hore, Nirjhar, Buchfelder, Michael, Savaskan, Nic E. and Eyupoglu, Ilker Y. (2014). Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration. Sci Rep, 4. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter-i.e. in non-cancerously transformed cells too-as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wolf, Ines M. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fan, Zheng UNSPECIFIED UNSPECIFIED UNSPECIFIED Rauh, Manfred UNSPECIFIED UNSPECIFIED UNSPECIFIED Seufert, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hore, Nirjhar UNSPECIFIED UNSPECIFIED UNSPECIFIED Buchfelder, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Savaskan, Nic E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eyupoglu, Ilker Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-428580
DOI:	10.1038/srep06226
Journal or Publication Title:	Sci Rep
Volume:	4
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GLUTAMATE; CELLS; TEMOZOLOMIDE; CANCER; GENES; NEURODEGENERATION; RADIOTHERAPY; ANGIOGENESIS; MECHANISMS; SUPPRESSOR Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42858