Thymoquinone Restores Radiation‐Induced TGF‐β Expression and Abrogates EMT in Chemoradiotherapy of Breast Cancer Cells

Abstract

Radiotherapy remains a prime approach to adjuvant therapies in patients with early and advanced breast cancer. In spite of therapeutic success, metastatic progression in patients undergoing therapy, limits its application. However, effective therapeutic strategies to understand the cellular and molecular machinery in inhibiting radiation-induced metastatic progression, which is poorly understood so far, need to be strengthened. Ionizing radiation was known to prompt cancer cell's metastatic ability by eliciting Transforming Growth Factor-beta (TGF-β), a key regulator in epithelial-mesenchymal transdifferentiation and radio-resistance. In this viewpoint, we employed thymoquinone as a radiosensitizer to investigate its migration and invasion reversal abilities in irradiated breast cancer cell lines by assessing their respective attributes. The role of metastasis regulatory molecules like TGF-β, E-cadherin, and integrin αV and its downstream molecules were determined using RT-PCR, western blotting, immunofluorescence, and extracellular TGF-β levels affirmed through ELISA assays. These studies affirmed the TGF-β restoring ability of thymoquinone in radiation-driven migration and invasion. Also, results demonstrated that the epithelial markers E-cadherin and cytokeratin 19 were downregulated whereas mesenchymal markers like integrin αV, MMP9, and MMP2 were upregulated by irradiation treatment; however thymoquinone pre-sensitization has reverted the expression of these proteins back to control proteins expression. Here, paclitaxel was chosen as an apoptosis inducer in TGF-β restored cells and confirmed its cytotoxic effects in radiation alone and thymoquinone sensitized irradiated cells. We conclude that this therapeutic modality is effective in preventing radiation-induced epithelial-mesenchymal transdifferentiation and concomitant induction of apoptosis in breast cancer.

DCST1-AS1 Promotes TGF-β-Induced Epithelial–Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1

“…MMP2 and MMP9 play an important role in cancer metastasis by promoting the degradation of extracellular matrix (13). TGF-β can enhance the tumorigenicity and invasiveness of breast cancer cells by inducing the expression of MMP2 and MMP9 (14). Using ELISA, we determined the levels of MMP2 and MMP9 in the cell culture supernatants before and after TGF-β treatment by plotting a concentration standard curve.…”

Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies

“…Treatment with TQ showed significant attenuation of tumorigenic signaling, including those mediated by TGF-β, VEGF, FGF, EGF, and several other pro-mitogenic, angiogenic, and metastatic factors, with a consequent dose-dependent inhibition of cancer cell growth, migration, and invasion (Yi et al, 2008; Ahmad et al, 2013; Khan et al, 2015; Rajput et al, 2015). It has also been reported that TQ can counteract the trauma-induced chemotaxis of circulating malignant cells and their epithelial to mesenchymal transition (EMT; Badr et al, 2011b; Ahmad et al, 2013; Khan et al, 2015).…”

“…Reelma et al confirmed that TQ can enhance the cytotoxic efficacy of radiation through modulation of cell cycle and apoptosis (Velho-Pereira et al, 2011). Another study reported the prevention of radiation-induced metastatic progression of breast cancer cells by TQ through restoration of TGF-β (Rajput et al, 2015). Moreover, it has been found that TQ can directly modulate the activation of several signal transduction pathways including PI3K-Akt-mTOR that are frequently upregulated in various cancers and confer resistance to radiotherapy (Baskar et al, 2014; Kundu et al, 2014b).…”

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

“…Notably, TQ has been reported to possess a wide range of biological activity including antitumor [10,11], anti-inflammation [12,13], anti-oxidation [14], and immunoregulatory effects [15]. Furthermore, the protective effect of TQ on MI/R injury has been demonstrated in numerous organs, including the liver [16], spinal cord [17], brain [18], kidney [19] and testis [20].…”