Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1
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Sebastian Krossa1, Anne Dorothée Schmitt2, Kirsten Hattermann3, Jürgen Fritsch4, Axel J. Scheidig1, Hubertus Maximilian Mehdorn2, Janka Held-Feindt2
1Institute of Zoology, Department of Structural Biology, 24118 Kiel, Germany
2Department of Neurosurgery, University of Schleswig-Holstein Medical Center, 24105 Kiel, Germany
3Department of Anatomy, University of Kiel, 24118 Kiel, Germany
4Institute of Immunology, University of Schleswig-Holstein Medical Center, 24105 Kiel, Germany
Janka Held-Feindt, e-mail: [email protected]
Keywords: akirin-2, twist-1, glioblastoma, chemoresistance
Received: January 16, 2015 Accepted: April 06, 2015 Published: April 18, 2015
The Twist-1 transcription factor and its interacting protein Akirin-2 regulate apoptosis. We found that in glioblastomas, highly malignant brain tumors, Akirin-2 and Twist-1 were expressed in glial fibrillary acidic protein positive tumor regions as well as in tumor endothelial cells and infiltrating macrophages / microglia. Temozolomide (TMZ) induced the expression of both molecules, partly shifting their nuclear to cytosolic localization. The knock-down (kd) of Akirin-2 increased the activity of cleaved (c)Caspase-3/-7, the amounts of cCaspases-3, -7 and cPARP-1 and resulted in an increased number of apoptotic cells after TMZ exposure. Glioblastoma cells containing decreased amounts of Akirin-2 after kd contained increased amounts of cCaspase-3 as determined by the ImageStreamx Mark II technology. For Twist-1, similar results were obtained with the exception that the combination of TMZ treatment and Twist-1 kd failed to significantly reduce chemoresistance compared with controls. This could be attributed to a cell population containing only slightly increased cCaspase-3 together with decreased Twist-1 levels, which was clearly larger than the respective population observed under Akirin-2 kd. Our results showed that, compared with Twist-1, Akirin-2 is the more promising target for RNAi strategies antagonizing Twist-1/Akirin-2 facilitated glioblastoma cell survival.
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