Covalent JNK Inhibitor, JNK-IN-8, Suppresses Tumor Growth in Triple-Negative Breast Cancer by Activating TFEB- and TFE3-Mediated Lysosome Biogenesis and Autophagy.

Autor:	Soleimani M; Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, Texas.; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Somma A; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Kaoud T; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas., Goyal R; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Bustamante J; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Wylie DC; Center for Biomedical Research Support, The University of Texas at Austin, Austin, Texas., Holay N; Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, Texas.; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Looney A; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Giri U; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Triplett T; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Dalby K; Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, Texas.; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas.; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas., Kowalski J; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Eckhardt SG; Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, Texas.; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas., Van Den Berg C; Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, Texas.; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas.; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2022 Oct 07; Vol. 21 (10), pp. 1547-1560.
DOI:	10.1158/1535-7163.MCT-21-1044
Abstrakt:	The heterogeneity and aggressiveness of triple-negative breast cancer (TNBC) contribute to its early recurrence and metastasis. Despite substantial research to identify effective therapeutic targets, TNBC remains elusive in terms of improving patient outcomes. Here, we report that a covalent JNK inhibitor, JNK-IN-8, suppresses TNBC growth both in vitro and in vivo. JNK-IN-8 reduced colony formation, cell viability, and organoid growth in vitro and slowed patient-derived xenograft and syngeneic tumor growth in vivo. Cells treated with JNK-IN-8 exhibited large, cytoplasmic vacuoles with lysosomal markers. To examine the molecular mechanism of this phenotype, we looked at the master regulators of lysosome biogenesis and autophagy transcription factor EB (TFEB) and TFE3. JNK-IN-8 inhibited TFEB phosphorylation and induced nuclear translocation of unphosphorylated TFEB and TFE3. This was accompanied by an upregulation of TFEB/TFE3 target genes associated with lysosome biogenesis and autophagy. Depletion of both TFEB and TFE3 diminished the JNK-IN-8-driven upregulation of lysosome biogenesis and/or autophagy markers. TFEB and TFE3 are phosphorylated by a number of kinases, including mTOR. JNK-IN-8 reduced phosphorylation of mTOR targets in a concentration-dependent manner. Knockout of JNK1 and/or JNK2 had no impact on TFEB/TFE3 activation or mTOR inhibition by JNK-IN-8 but inhibited colony formation. Similarly, reexpression of either wildtype or drug-nonbinding JNK (C116S) in JNK knockout cells did not reverse JNK-IN-8-induced TFEB dephosphorylation. In summary, JNK-IN-8 induced lysosome biogenesis and autophagy by activating TFEB/TFE3 via mTOR inhibition independently of JNK. Together, these findings demonstrate the efficacy of JNK-IN-8 as a targeted therapy for TNBC and reveal its novel lysosome- and autophagy-mediated mechanism of action. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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