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Temozolomide‐modulated glioma proteome: Role of interleukin‐1 receptor‐associated kinase‐4 ( IRAK 4) in chemosensitivity
Author(s) -
Kumar Durairaj M.,
Patil Vikas,
Ramachandran Bini,
Nila Murugesan V.,
Dharmalingam Kuppamuthu,
Somasundaram Kumaravel
Publication year - 2013
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.201200261
Subject(s) - temozolomide , glioma , gene knockdown , downregulation and upregulation , cancer research , biology , signal transduction , cell culture , microbiology and biotechnology , gene , biochemistry , genetics
The current treatment for glioblastoma includes temozolomide ( TMZ ) chemotherapy, yet the mechanism of action of TMZ is not thoroughly understood. Here, we investigated the TMZ ‐induced changes in the proteome of the glioma‐derived cell line ( U 251) by 2 D DIGE . We found 95 protein spots to be significantly altered in their expression after TMZ treatment. MS identified four upregulated spots: aspartyl t RNA synthetase glutathione synthetase, interleukin‐1 receptor‐associated kinase‐4 ( IRAK 4), and breast carcinoma amplified sequence‐1 and one downregulated spot: optineurin. TMZ ‐induced regulation of these five genes was validated by RT ‐q PCR and W estern blot analysis. RNA i‐mediated knockdown of IRAK 4, an important mediator of T oll‐like receptors signaling and chemoresistance, rendered the glioma cells resistant to TMZ . High levels of IRAK 4 induced upon TMZ treatment resulted in IRAK 1 downregulation and inhibition of NF k B pathway. Endogenous IRAK 4 protein, but not transcript levels in glioma cell lines, correlated with TMZ sensitivity. Thus, we have identified several TMZ ‐modulated proteins and discovered an important novel role for IRAK 4 in determining TMZ sensitivity of glioma cells through its ability to inhibit T oll‐like receptor signaling and NF k B pathway.