Lonidamine and domperidone inhibit expansion of transformed cell areas by modulating motility of surrounding nontransformed cells

• Published in: The Journal of biological chemistry Vol. 298; no. 12; p. 102635
• Main Authors: Aoyama, Megumi, Ishikawa, Kosuke, Nemoto, Shuntaro, Hirano, Hiroyuki, Watanabe, Nobumoto, Osada, Hiroyuki, Watanabe, Shinya, Semba, Kentaro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2022; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; anticancer drugs; Antineoplastic Agents - pharmacology; cell motility; domperidone; Domperidone - pharmacology; drug screening; Drug Screening Assays, Antitumor; Epithelial Cells; Indazoles - pharmacology; lonidamine; Mammary Glands, Animal - cytology; Mice; Neoplasms - drug therapy; Neoplasms - pathology; oncogene; proliferation; MPC; LND; proliferation; drug screening; DMSO; CIL; HRP; lonidamine; epithelial cells; DN; oncogene; DOX; anticancer drugs; cell motility; domperidone; DPD; CA; NMuMG
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2022.102635

Cancer cells intrinsically proliferate in an autonomous manner; however, the expansion of cancer cell areas in a tissue is known to be regulated by surrounding nontransformed cells. Whether these nontransformed cells can be targeted to control the spread of cancer cells is not understood. In this study, we established a system to evaluate the cancer-inhibitory activity of surrounding nontransformed cells and screened chemical compounds that could induce this activity. Our findings revealed that lonidamine (LND) and domperidone (DPD) inhibited expansion of oncogenic foci of KRASG12D-expressing transformed cells, whereas they did not inhibit the proliferation of monocultured KRASG12D-expressing cells. Live imaging revealed that LND and DPD suppressed the movement of nontransformed cells away from the attaching cancer cells. Moreover, we determined that LND and DPD promoted stress fiber formation, and the dominant-negative mutant of a small GTPase RhoA relieved the suppression of focus expansion, suggesting that RhoA-mediated stress fiber formation is involved in the inhibition of the movement of nontransformed cells and focus expansion. In conclusion, we suggest that elucidation of the mechanism of action of LND and DPD may lead to the development of a new type of drug that could induce the anticancer activity of surrounding nontransformed cells.