ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition
| Autor: | Keisuke Tazuru, Kei Kozawa, Nobuhito Goda, Shiyu Ayukawa, Takashi Hayashi, Ayana Sasaki, Sayuri Iijima, Susumu Ishikawa, Takeshi Maruyama, Tomoko Morita, Yasuyuki Fujita, Norikazu Hashimoto, Nanami Sato |
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| Jazyk: | japonština |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
2019-20 coronavirus outbreak media_common.quotation_subject Cell 02 engineering and technology medicine.disease_cause Competition (biology) Article law.invention 03 medical and health sciences Confocal microscopy law medicine Apical extrusion lcsh:Science media_common Cancer Gene knockdown Multidisciplinary Chemistry Biological Sciences 021001 nanoscience & nanotechnology medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure lcsh:Q 0210 nano-technology Carcinogenesis |
| Zdroj: | iScience iScience, Vol 23, Iss 7, Pp 101327-(2020) |
| ISSN: | 2589-0042 |
| Popis: | Summary Previous studies have revealed that, at the initial step of carcinogenesis, transformed cells are often eliminated from epithelia via cell competition with the surrounding normal cells. In this study, we performed cell competition-based high-throughput screening for chemical compounds using cultured epithelial cells and confocal microscopy. PLX4720 was identified as a hit compound that promoted apical extrusion of RasV12-transformed cells surrounded by normal epithelial cells. Knockdown/knockout of ZAK, a target of PLX4720, substantially enhanced the apical elimination of RasV12 cells in vitro and in vivo. ZAK negatively modulated the accumulation or activation of multiple cell competition regulators. Moreover, PLX4720 treatment promoted apical elimination of RasV12-transformed cells in vivo and suppressed the formation of potentially precancerous tumors. This is the first report demonstrating that a cell competition-promoting chemical drug facilitates apical elimination of transformed cells in vivo, providing a new dimension in cancer preventive medicine. Graphical Abstract Highlights • A cell competition-based high-throughput screen identifies chemical enhancers • PLX4720 enhances the apical elimination of RasV12 cells via ZAK inhibition • ZAK negatively modulates cell competition regulators • PLX4720 treatment promotes apical elimination of RasV12 cells in vivo Chemistry; Biological Sciences; Cancer |
| Databáze: | OpenAIRE |
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