Abstract
Triple-negative breast cancers (TNBCs) constitute a heterogeneous subtype of breast cancers that present a significant challenge for the treatment and management, and have a poor clinical outcome. Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical calcium/calmodulin (Ca2++/CaM)-dependent Ser/Thr-kinase that regulates peptide chain elongation by phosphorylating its substrate elongation factor 2 (eEF2), resulting in decreased protein translation. Recently, we have reported that eEF-2K expression is significantly upregulated in TNBC cell lines and is associated with poor survival and worse prognosis, indicating that eEF-2K is a potential therapeutic target in TNBC. Moreover, we demonstrated that eEF-2K promotes TNBC cell proliferation, invasion/migration, and tumorigenesis. Its inhibition by systemically administered liposomal siRNA resulted in marked inhibition of tumor growth and enhancement in the efficacy of chemotherapy in orthotopic TNBC mouse models (Tekedereli 2012). Currently, there are no reported inhibitors of eEF-2K. Natural dietary poly phenolic compounds have been shown to inhibit various cancers by regulating various kinases and molecular targets, with both in-vitro and in-vivo activity. Thymoquinone (TQ) is an active ingredient isolated from Nigella sativa and has been investigated for its antioxidant, anti-inflammatory, and anticancer activities in several in-vitro and in-vivo models. However, the mechanism by which TQ mediates its effects not well understood. Here, we investigated if TQ inhibits eEF-2K in TNBC cells. We demonstrated, for the first time, that treatment with TQ decreases the expression of eEF-2K in a dose dependent manner as wells as its downstream targets, resulting in decreased proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, eEF-2K knockdown by siRNA recapitulates the effects of TQ, including cell proliferation, migration/invasion, and correlated events. Additionally, TQ treatment inhibits Src activity and other molecular targets, and induces significant apoptosis in TNBC cells in a caspase independent manner. Currently, we are investigating the downstream effects of TQ by RPPA analysis and its in-vivo efficacy in orthotopic xenograft mouse models of TNBC. Overall, our studies suggest that TQ could present a novel therapeutic strategy in targeting eEF-2K and inhibition of TNBCs.
Citation Format: Nashwa N. Kabil, Recep Bayraktar, Nermin Kahraman, Bulent Ozpolat. Targeting eEF-2Kinase by thymoquinone in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2176.
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