Sterol Regulatory Element-Binding Protein 1 (SREBP-1) Inhibitors Arrest Tumour Growth in Glioblastoma Multiforme (T98G) and Human pancreatic carcinoma (MIA PaCa-2) Cell Lines.
Siqingaowa, Anna 1986-
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ABSTRACT Glioblastoma multiforme (GBM) is the most aggressive and prevalent type of primary malignant brain tumour of the central nervous system, predominantly affecting adults. The current medical treatment for GBM is surgical resection combined with ionizing radiation (IR) and/or chemotherapeutic with temozolomide. However, this treatment is proved to be insufficient as it only provides GBM patients with a one year survival period post-diagnosis. GBM cells have been found to develop resistance to temozolomide treatment. Therefore, the discovery of novel therapeutic agents that possess the capability to pass through the blood brain barrier is warranted in the effective management of GBM. Sterol regulatory element-binding protein 1 (SREBP-1) is a key transcription factor involved in the regulation of lipogenesis through regulating gene expression of proteins involved in fatty acid biosynthesis. In GBM and many other cancer types, overexpression of SREBP-1 has been found to be associated with its aggressive pathological features. Therefore, SREBPs can be potential targets for therapeutic treatment in GBM. We hypothesize that Indip and other SREBP1 inhibitors such as PF429242 and fatostatin arrest the proliferation of cells in a well-established model of GBM cells, the T98G cell line, maintained in vitro in culture. The present study investigates the efficacy of SREBP-1 inhibitors such as fatostatin, PF429242 and a recently designed short cell penetrating bioactive TAT-fused peptide, indip, in inhibiting the activation of SREBP-1 protein as well as proliferation of T98G cells. All three compounds, fatostatin, PF 429242 and indip led to significant reduction in T98G cell growth in a concentration and time-dependent manner. Our data confirmed that this effect is due to inhibition of SREBP-1 activation that led to T98G cell line apoptosis resulting in reduction in cell size, cell migration and tumor sphere growth. The apoptotic death induced in T98G cells was supported by a more than two fold increase in caspase-3 activity. The three drugs employed arrested the proliferation of T98G cell line in the G2/M phase of the cell cycle. The inhibition of SREBP-1 resulted in significant suppression of expression of key downstream lipogenesis enzymes, Stearoyl-CoA desaturase-1, fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase in both GBM (T98G) and human pancreatic carcinoma (MIA PaCa-2) cells. Furthermore, the combination of Indip (indirect) and PF429242 (direct) treatment had the greatest effect on promoting apoptosis (87% cell death), compared to single drug treatment (40 % by Indip alone and 60% by PF429242). These data suggest that combination treatment with SREBP-1 inhibitor(s) along with temozolomide could be considered as a novel therapeutic approach in the effective management of GBM.
DegreeMaster of Science (M.Sc.)
CommitteeBardal, Stan; Venkat, Venkat; Uppalapati, Maruti Chandra; Vizeacoumar, Franco
Copyright DateAugust 2017
Sterol Regulatory Element-Binding Protein 1 (SREBP-1)