ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition

Takeshi Maruyama*, Ayana Sasaki, Sayuri Iijima, Shiyu Ayukawa, Nobuhito Goda, Keisuke Tazuru, Norikazu Hashimoto, Takashi Hayashi, Kei Kozawa, Nanami Sato, Susumu Ishikawa, Tomoko Morita, Yasuyuki Fujita

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number101327
JournaliScience
Volume23
Issue number7
DOIs
Publication statusPublished - 2020 Jul 24

Keywords

  • Biological Sciences
  • Cancer
  • Chemistry

ASJC Scopus subject areas

  • General

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