Abstract
BackgroundPrevious reports have shown an antiproliferative effect of the synthetic, 3-thia fatty acid tetradecylthioacetic acid (TTA) on different cancer cells in vitro and in vivo. The mechanisms behind the observed effects are poorly understood. We therefore wanted to explore the molecular mechanisms involved in TTA-induced growth inhibition of the human colon cancer cell line SW620 by gene expression profiling.MethodsAn antiproliferative effect of TTA on SW620 cells in vitro was displayed in real time using the xCELLigence System (Roche). Affymetrix gene expression profiling was performed to elucidate the molecular mechanisms behind the antiproliferative effect of TTA. Changes in gene expression were verified at protein level by western blotting.ResultsTTA reduced SW620 cell growth, measured as baseline cell index, by 35% and 55% after 48 h and 72 h, respectively. We show for the first time that TTA induces an endoplasmic reticulum (ER) stress response in cancer cells. Gene expression analysis revealed changes related to ER stress and unfolded protein response (UPR). This was verified at protein level by phosphorylation of eukaryote translation initiation factor 2 alpha (eIF2α) and downstream up-regulation of activating transcription factor 4 (ATF4). Transcripts for positive and negative cell cycle regulators were down- and up-regulated, respectively. This, together with a down-regulation of Cyclin D1 at protein level, indicates inhibition of cell cycle progression. TTA also affected transcripts involved in calcium homeostasis. Moreover, mRNA and protein level of the ER stress inducible C/EBP-homologous protein (CHOP), Tribbles homolog 3 (Drosophila) (TRIB3) and CCAAT/enhancer binding protein beta (C/EBPβ) were enhanced, and the C/EBPβ LIP/LAP ratio was significantly increased. These results indicate prolonged ER stress and a possible link to induction of cell death.ConclusionWe find that TTA-induced growth inhibition of SW620 cells seems to be mediated through induction of ER stress and activation of the UPR pathway.
Highlights
Previous reports have shown an antiproliferative effect of the synthetic, 3-thia fatty acid tetradecylthioacetic acid (TTA) on different cancer cells in vitro and in vivo
By using gene expression analysis, we found that DHA induces extensive changes in the expression of transcripts involved in biological pathways like endoplasmic reticulum (ER) stress and unfolded protein response (UPR), protein degradation, Ca2+ homeostasis, cell cycle progression and apoptosis [28]
TTA induces extensive changes at mRNA level indicating ER stress and UPR In an attempt to unravel the mechanisms underlying the growth-inhibiting effect of TTA, SW620 cells were cultivated in the absence or presence of 75 μM TTA for 24 h, followed by gene expression profiling
Summary
Previous reports have shown an antiproliferative effect of the synthetic, 3-thia fatty acid tetradecylthioacetic acid (TTA) on different cancer cells in vitro and in vivo. We wanted to explore the molecular mechanisms involved in TTA-induced growth inhibition of the human colon cancer cell line SW620 by gene expression profiling. TTA has been found to inhibit growth of glioma [11,12], leukemia [13,14,15,16] and colon cancer cell lines [11,17] in vitro and in vivo, and hepatoma [18] and breast cancer cells [19] in vitro. TTA seems to be more potent in reducing cell growth compared with the omega-3 (n-3) PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [20]. TTA food supplementation seems to be generally well tolerated by healthy persons [15,21], and TTA may have a potential in cancer treatment alone or in combination with other therapies
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