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ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition
Takeshi Maruyama1, Ayana Sasaki2, Sayuri Iijima2
1Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan; Waseda Institute for Advanced Study, Waseda University, Tokyo 169-8050, Japan.
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.
Insights
This study found that PLX4720 promotes the elimination of precancerous cells through cell competition. Targeting ZAK enhances this process, offering a new approach for cancer prevention.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Carcinogenesis involves the elimination of transformed cells via cell competition.
- Understanding this process is crucial for developing cancer prevention strategies.
Purpose of the Study:
- To identify chemical compounds that promote the elimination of transformed cells through cell competition.
- To investigate the role of ZAK in cell competition and its modulation by PLX4720.
Main Methods:
- High-throughput screening of chemical compounds using cultured epithelial cells.
- Confocal microscopy to observe apical extrusion of transformed cells.
- In vitro and in vivo experiments involving gene knockdown/knockout and drug treatment.
Main Results:
- PLX4720 was identified as a compound promoting apical extrusion of RasV12-transformed cells.
- Knockdown/knockout of ZAK enhanced the apical elimination of transformed cells.
- PLX4720 treatment suppressed tumor formation in vivo.
Conclusions:
- PLX4720 facilitates the apical elimination of transformed cells via cell competition in vivo.
- Targeting ZAK enhances this elimination process.
- This study presents a novel strategy for cancer preventive medicine by leveraging cell competition.
