Biomedicines (Jun 2022)

<i>Citrus limon</i> <i>L</i>.-Derived Nanovesicles Show an Inhibitory Effect on Cell Growth in p53-Inactivated Colorectal Cancer Cells via the Macropinocytosis Pathway

  • Hideki Takakura,
  • Toshimasa Nakao,
  • Takumi Narita,
  • Mano Horinaka,
  • Yukako Nakao-Ise,
  • Tetsushi Yamamoto,
  • Yosuke Iizumi,
  • Motoki Watanabe,
  • Yoshihiro Sowa,
  • Keisuke Oda,
  • Nobuhiro Mori,
  • Toshiyuki Sakai,
  • Michihiro Mutoh

DOI
https://doi.org/10.3390/biomedicines10061352
Journal volume & issue
Vol. 10, no. 6
p. 1352

Abstract

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Edible plant-derived nanovesicles have been explored as effective materials for preventing colorectal cancer (CRC) incidence, dependent on gene status, as a K-Ras-activating mutation via the macropinocytosis pathway. Approximately 70% of CRC harbors the p53 mutation, which is strongly associated with a poor prognosis for CRC. However, it has not been revealed whether p53 inactivation activates the macropinocytosis pathway or not. In this study, we investigated parental cells, wild-type or null for p53 treated with Citrus limon L.-derived nanovesicles, as potential materials for CRC prevention. Using ultracentrifugation, we obtained C. limon L.-derived nanovesicles, the diameters of which were approximately 100 nm, similar to that of the exosomes derived from mammalian cells. C. limon L.-derived nanovesicles showed inhibitory effects on cell growth in not p53-wild, but also in p53-inactivated CRC cells. Furthermore, we revealed that the macropinocytosis pathway is activated by p53 inactivation and C. limon L.-derived nanovesicles were up taken via the macropinocytosis pathway. Notably, although C. limon L.-derived nanovesicles contained citrate, the inhibitory effects of citrate were not dependent on the p53 status. We thus provide a novel mechanism for the growth inhibition of C. limon L.-derived nanovesicles via macropinocytosis and expect to develop a functional food product containing them for preventing p53-inactivation CRC incidence.

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