|SUSWAM, ESTHER - University Of Alabama|
|SHACKA, JOHN - University Of Alabama|
|WALKER, KIERA - University Of Alabama|
|LU, LIANG - University Of Alabama|
|LI, XUELIN - University Of Alabama|
|SI, YING - University Of Alabama|
|ZHANG, XIAOWEN - University Of Alabama|
|ZHENG, LEI - University Of Alabama|
|NABORS, L - University Of Alabama|
|KING, PETER - University Of Alabama|
Submitted to: Journal of Neuro-Oncology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/12/2013
Publication Date: 6/1/2013
Publication URL: http://handle.nal.usda.gov/10113/57433
Citation: Suswam, E.A., Shacka, J.J., Walker, K., Lu, L., Li, X., Si, Y., Zhang, X., Zheng, L., Nabors, L.B., Cao, H., King, P.H. 2013. Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth. Journal of Neuro-Oncology. 113(2):195-205.
Interpretive Summary: Various types of cancers, Alzheimer’s disease, arthritis, cardiovascular diseases, and diabetes affect millions of people today. Cytokines including tumor necrosis factor alpha (TNF) are important in the development and progression of these diseases. However, anti-TNF therapies targeting TNF and its receptors failed in trials. An alternative strategy to reduce pro-inflammatory cytokines in the relevant tissues is to promote degradation of multiple cytokine mRNAs; owing to the facts that these mRNAs possess AU-rich elements (AREs) and that their stabilities are largely controlled by ARE binding proteins. Tristetraprolin (TTP), an anti-inflammatory protein, binds to the AREs of clinically important mRNAs such as TNF mRNA and promotes the destruction of those transcripts. In mice, TTP deficiency causes a profound inflammatory syndrome with cachexia, dermatitis, erosive arthritis, autoimmunity and myeloid hyperplasia, due to excessive production of TNF and other cytokines. Previous studies have shown that TTP is phosphorylated extensively in intact cells. However, limited information is available about the effects of these phosphorylation sites on cancer cell growth. In this study, we discovered that mutant TTP serves as a potent inhibitor of malignant glioma cell growth. Additional studies in this area may provide useful information for cancer therapy.
Technical Abstract: Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one mechanism for upregulating these and other growth factors. In glioma cells, we have shown that the post-transcriptional machinery is optimized for growth factor upregulation secondary to overexpression of the mRNA stabilizer, HuR. The negative regulator, tristetraprolin (TTP), on the other hand, may be suppressed because of extensive phosphorylation. Here we test that possibility by analyzing the phenotypic effects of a mutated form of TTP (mt-TTP) in which 8 phosphoserine residues were converted to alanines. We observed a significantly enhanced negative effect on growth factor expression in glioma cells at the post-transcriptional and transcriptional levels. The protein became stabilized and displayed significantly increased antiproliferative effects compared to wild-type TTP. Macroautophagy was induced with both forms of TTP, but inhibition of autophagy did not affect cell viability. We conclude that glioma cells suppress TTP function through phosphorylation of critical serine residues which in turn contributes to growth factor upregulation and tumor progression.