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KMID : 0578320230460060387
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Molecules and Cells
2023 Volume.46 No. 6 p.387 ~ p.398
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Microtubule Acetylation-Specific Inhibitors Induce Cell Death and Mitotic Arrest via JNK/AP-1 Activation in Triple-Negative Breast Cancer Cells
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Ahn Su-Yeon
Kwon Ah-Reum
Oh Young-Soo
Rhee Sang-Myung
Song Woo-Keun
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Abstract
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Microtubule acetylation has been proposed as a marker of highly heterogeneous and aggressive triple-negative breast cancer (TNBC). The novel microtubule acetylation inhibitors GM-90257 and GM-90631 (GM compounds) cause TNBC cancer cell death but the underlying mechanisms are currently unknown. In this study, we demonstrated that GM compounds function as anti-TNBC agents through activation of the JNK/AP-1 pathway. RNA-seq and biochemical analyses of GM compound-treated cells revealed that c-Jun N-terminal kinase (JNK) and members of its downstream signaling pathway are potential targets for GM compounds. Mechanistically, JNK activation by GM compounds induced an increase in c-Jun phosphorylation and c-Fos protein levels, thereby activating the activator protein-1 (AP-1) transcription factor. Notably, direct suppression of JNK with a pharmacological inhibitor alleviated Bcl2 reduction and cell death caused by GM compounds. TNBC cell death and mitotic arrest were induced by GM compounds through AP-1 activation in vitro. These results were reproduced in vivo, validating the significance of microtubule acetylation/JNK/AP-1 axis activation in the anti-cancer activity of GM compounds. Moreover, GM compounds significantly attenuated tumor growth, metastasis, and cancer-related death in mice, demonstrating strong potential as therapeutic agents for TNBC.
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KEYWORD
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JNK/AP-1 signaling, microtubule acetylation, triple-negative breast cancer
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