Down-regulation of the inhibitor of growth 1 (ING1) tumor suppressor sensitizes p53-deficient glioblastoma cells to cisplatin-induced cell death.
Impaired tumor suppressor functions, such as deficient p53, are characteristic for glioblastoma multiforme (GBM) and can cause resistance to DNA-damaging agents like cisplatin. We have recently shown that the INhibitor of Growth 1 (ING1) tumor suppressor is down-regulated in malignant gliomas and that the decrease of ING1 expression correlates with histological grade of malignancy, suggesting a role for ING1 in the pathogenesis and progression of malignant gliomas. Based on this background, the purpose of our current study was to examine the potential impact of ING1 protein levels on DNA-damage response in GBM. Using LN229 GBM cells, which express ING1 proteins and harbor mutant TP53, we are the first to show that DNA damage by cisplatin or ionizing radiation differentially induced the two major ING1 splicing isoforms. The p47 ING1a isoform, that promotes deacetylation of histones, thus formation of heterochromatic regions of DNA, which are less susceptible to DNA damage, was preferentially induced by >50-fold. This might represent a response to protect DNA from damage. Also, ING1 knockdown by siRNA accelerated transit of cells through G1 phase, consistent with ING1 serving a tumor suppressor function, and caused cells to enter apoptosis more rapidly in response to cisplatin. Our results indicate that malignant gliomas may down-regulate ING1 to allow more efficient tumor growth and progression. Also, ING1 down-regulation may sensitize GBM cells with deficient p53 to treatment with cisplatin.
Tallen
Ute Gesche
UG
Department of Pediatric Oncology and Hematology, Children's Hospital, Charité, Universitätsmedizin-Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. gesche.tallen@charite.de
Truss
Matthias
M
Kunitz
Frank
F
Wellmann
Sven
S
Unryn
Brad
B
Sinn
Brigitte
B
Lass
Ulrike
U
Krabbe
Sonja
S
Holtkamp
Nikola
N
Hagemeier
Christian
C
Wurm
Reinhard
R
Henze
Guenter
G
Riabowol
Karl T
KT
von Deimling
Andreas
A
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011827:Radiation; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D001973:Bromodeoxyuridine; D002945:Cisplatin