A novel triazole, NMK-T-057, induces autophagic cell death in breast cancer cells by inhibiting {gamma}-secretase-mediated activation of Notch signaling [Signal Transduction]
Notch signaling is reported to be deregulated in several malignancies, including breast, and the enzyme γ-secretase plays an important role in the activation and nuclear translocation of Notch intracellular domain (NICD). Hence, pharmacological inhibition of γ-secretase might lead to the subsequent inhibition of Notch signaling in cancer cells. In search of novel γ-secretase inhibitors (GSIs), we screened a series of triazole-based compounds for their potential to bind γ-secretase and observed that 3-(3′4′,5′-trimethoxyphenyl)-5-(N-methyl-3′-indolyl)-1,2,4-triazole compound (also known as NMK-T-057) can bind to γ-secretase complex. Very interestingly, NMK-T-057 was found to inhibit proliferation, colony-forming ability, and motility in various breast cancer (BC) cells such as MDA-MB-231, MDA-MB-468, 4T1 (triple-negative cells), and MCF-7 (estrogen receptor (ER)/progesterone receptor (PR)–positive cell line) with negligible cytotoxicity against noncancerous cells (MCF-10A and peripheral blood mononuclear cells). Furthermore, significant induction of apoptosis and inhibition of epithelial-to-mesenchymal transition (EMT) and stemness were also observed in NMK-T-057–treated BC cells. The in silico study revealing the affinity of NMK-T-057 toward γ-secretase was further validated by a fluorescence-based γ-secretase activity assay, which confirmed inhibition of γ-secretase activity in NMK-T-057–treated BC cells. Interestingly, it was observed that NMK-T-057 in...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Amlan Das, Maruthi Kumar Narayanam, Santanu Paul, Pritha Mukhnerjee, Suvranil Ghosh, Debabrata Ghosh Dastidar, Subhendu Chakrabarty, Arnab Ganguli, Biswarup Basu, Mahadeb Pal, Urmi Chatterji, Sushanta K. Banerjee, Parimal Karmakar, Dalip Kumar, Gopal Chak Tags: Cell Biology Source Type: research
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