Toll-Iike Receptor-3 Activation Enhances Malignant Traits in Human Breast Cancer Cells Through Hypoxia-inducible Factor-1α

Abstract

Background/Aim: Hypoxia-inducible factor 1 (HIF1) inhibitors have been proposed as therapeutic agents for several tumor types. HIF1α is induced by hypoxia and by pathogens in normoxia through toll-like receptors (TLRs). The TLR3 activator polyinosinic:polycytidylic acid [poly(I:C)] induces apoptosis in various types of cancer but not in the most aggressive breast cancer cell lines. We hypothesized that the failure of TLR3 stimulation to induce apoptosis in these cells might be due to an elevated HIF1α level and this link might be exploited. Materials and Methods: Poly(I:C)-induced signaling pathway and expression of HIF1α and HIF1α targets were studied in MDA MB-231 and MCF-7 breast cancer cell lines by western blot. Flow cytometry was used for apoptotic responses and vasculogenic mimicry as bioassay. Results: Poly(I:C) increased expression of HIF1α and its targets BCL2 apoptosis regulator and c-MYC. Moreover, using pharmacological or genetic HIF1 inhibition, reduction of poly(I:C)-induced expression of HIF1α was paralleled by lowering of c-MYC and increased sensitivity to poly(I:C)-induced apoptosis, demonstrating the crucial role of this factor. We provide the first evidence in breast cancer cells that TLR3 stimulation induces HIF1αdependent vasculogenic mimicry. By using specific inhibitors, we identified a signaling cascade upstream of HIF1α induction. Conclusion: Combined treatment with poly(I:C) and HIF1 inhibitors deserves consideration as an effective strategy in breast cancer therapy.

Immunostimulant Bathing Influences the Expression of Immune- and Metabolic-Related Genes in Atlantic Salmon Alevins

“…Moreover, HIF1A has been found to be highly expressed during Poly I:C stimulation in mandarin fish (Siniperca chuatsi) [99]. MYC (and HIF1A) has previously been found to be highly expressed in human breast cancer cells treated with Poly I:C [100]. Lastly, expression of SLC2A1 (GLUT1) has been shown to be induced in RAW macrophages stimulated by Poly I:C, indicative of increased glycolysis [101].…”

Acriflavine, an Acridine Derivative for Biomedical Application: Current State of the Art

“…Therefore, it is important to use ACF in order to inhibit not only TLR3 signaling but also HIF-1, leading to increased effectiveness in breast cancer treatment. 98 Melanoma can also activate hypoxia response pathways even under normoxic conditions, indicating the participation of HIF-1α enabling survival under oxidative stress. 99 The influence of ACF on the metabolism and progression of melanoma under normoxic conditions was described ( Figure 7 ).…”

“…These are, for example, cytokines or TLR proteins that induce tumor progression. Therefore, it is important to use ACF in order to inhibit not only TLR3 signaling but also HIF-1, leading to increased effectiveness in breast cancer treatment . Melanoma can also activate hypoxia response pathways even under normoxic conditions, indicating the participation of HIF-1α enabling survival under oxidative stress .…”