Inhibiting Translation Elongation with SVC112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma.

Autor:	Keysar SB; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Gomes N; SuviCa, Inc., Boulder, Colorado., Miller B; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Jackson BC; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Le PN; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Morton JJ; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Reisinger J; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Chimed TS; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Gomez KE; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Nieto C; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado., Frederick B; SuviCa, Inc., Boulder, Colorado., Pronk GJ; SuviCa, Inc., Boulder, Colorado., Somerset HL; Department of Pathology, University of Colorado School of Medicine, and VA Medical Center, Aurora, Colorado., Tan AC; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.; Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, Colorado., Wang XJ; Department of Pathology, University of Colorado School of Medicine, and VA Medical Center, Aurora, Colorado.; Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado., Raben D; Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado., Su TT; SuviCa, Inc., Boulder, Colorado. antonio.jimeno@ucdenver.edu Tin.Su@colorado.edu.; Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado., Jimeno A; Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. antonio.jimeno@ucdenver.edu Tin.Su@colorado.edu.; Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Mar 01; Vol. 80 (5), pp. 1183-1198. Date of Electronic Publication: 2020 Jan 07.
DOI:	10.1158/0008-5472.CAN-19-3232
Abstrakt:	Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. SIGNIFICANCE: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu