Role of delta-like ligand-4 in chemoresistance against docetaxel in MCF-7 cells

Abstract

<jats:p> As Notch receptors have been shown to induce chemoresistance, we hypothesized that delta-like ligand-4 (DLL4), a central Notch signalling ligand, might also participate in chemoresistance in breast cancer. To investigate this issue, overexpression of DLL4 was induced by transfection with expression vectors for DLL4 in the human breast cancer cell line Michigan cancer foundation-7 (MCF-7). It was found that DLL4 could be adaptively upregulated by docetaxel (DOC) treatment in a dose-dependent manner, but Notch1 was unaffected. Overexpression of DLL4 could significantly attenuate the cytotoxic effects of DOC by increasing Bcl-2 expression, while decreasing Bax expression, apoptosis rate and DNA damage. The protective effects of DLL4 made cells acquire chemoresistance against DOC and resulted in cancer cell survival. DLL4 is normally regarded as a regulator of vascular development. Our results expanded the understanding of DLL4. Since DLL4 may play an important role in the process of acquiring chemoresistance, it may be a promising target in overcoming chemoresistance in breast cancer. </jats:p>

The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance

“…Similar to receptors, higher expression of Notch signaling ligands such as DLL4 was detected in a docetaxal-resistant luminal ER + luminal MCF-7 breast cancer cell line with increased CSC activity (Wang et al 2017). Moreover, DLL4 is an important biomarker of chemoresistant breast cancer subtypes (Hoey et al 2009;Wang et al 2017).…”

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…72 DLL4 is overexpressed in the plasma and tumor tissue of BC patients and is associated with a poor outcome, metastasis and drug resistance. [73][74][75][76][77] The inhibition of DLL4 by RGD peptide-modified lipid nanoparticles (RGD-LNPs) encapsulating siRNA prolongs the OS of mouse models of BC with lung metastasis. 78 In addition, lung metastasis in BC can be inhibited by the anti-cancer therapeutic peptides AD-01 and ALM201, which downregulate DLL4 and Notch4.…”

“…118,119 The effects of DLL4 are profound, not only affecting tumor angiogenesis, but also regulating cell behavior. DLL4 permits sustained Notch activation and promotes the crosstalk between tumor cells (T-T), 49,73,88,[120][121][122][123][124][125] ECs and ECs (E-E), 98,[126][127][128] tumor cells and ECs (T-E) 43,97,[129][130][131][132] (Figure 3). The three main oncogenic pathways including NF-κB, PI3K/Akt and MMP-2/9 signaling are potential therapy targets that are activated by DLL4/Notch signaling through T-T and T-E interactions.…”

A “NOTCH” Deeper into the Epithelial-To-Mesenchymal Transition (EMT) Program in Breast Cancer

“…For instance, Notch receptors (Notch-1/2/3/4) interact with the epidermal growth factor receptor tyrosine kinase family (RTK) of proteins, such as HER-1, 2, 3 and 4. Over-expressions of HER and/or Notch activity have been reported in BC, thereby identifying Notch as a potent oncogene capable of advancing malignant state in BC [8]. Moreover, Notch maintains HER-induced downstream signals radiated to pathways such as mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K).…”