Inhibiting the MCM8-9 complex selectively sensitizes cancer cells to cisplatin and olaparib

Issay Morii, Yukiko Iwabuchi, Sumiko Mori, Masaki Suekuni, Toyoaki Natsume, Kazumasa Yoshida, Nozomi Sugimoto, Masato T. Kanemaki, Masatoshi Fujita

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4 Citations (Scopus)

Abstract

MCM8 and MCM9 are paralogues of the MCM2-7 eukaryotic DNA replication helicase proteins and play a crucial role in a homologous recombination-mediated repair process to resolve replication stress by fork stalling. Thus, deficiency of MCM8-9 sensitizes cells to replication stress caused, for example, by platinum compounds that induce interstrand cross-links. It is suggested that cancer cells undergo more replication stress than normal cells due to hyperstimulation of growth. Therefore, it is possible that inhibiting MCM8-9 selectively hypersensitizes cancer cells to platinum compounds and poly(ADP-ribose) polymerase inhibitors, both of which hamper replication fork progression. Here, we inhibited MCM8-9 in transformed and nontransformed cells and examined their sensitivity to cisplatin and olaparib. We found that knockout of MCM9 or knockdown of MCM8 selectively hypersensitized transformed cells to cisplatin and olaparib. In agreement with reported findings, RAS- and human papilloma virus type 16 E7-mediated transformation of human fibroblasts increased replication stress, as indicated by induction of multiple DNA damage responses (including formation of Rad51 foci). Such replication stress induced by oncogenes was further increased by knockdown of MCM8, providing a rationale for cancer-specific hypersensitization to cisplatin and olaparib. Finally, we showed that knocking out MCM9 increased the sensitivity of HCT116 xenograft tumors to cisplatin. Taken together, the data suggest that conceptual MCM8-9 inhibitors will be powerful cancer-specific chemosensitizers for platinum compounds and poly(ADP-ribose) polymerase inhibitors, thereby opening new avenues to the design of novel cancer chemotherapeutic strategies.

Original languageEnglish
Pages (from-to)1044-1053
Number of pages10
JournalCancer Science
Volume110
Issue number3
DOIs
Publication statusPublished - Mar 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Morii, I., Iwabuchi, Y., Mori, S., Suekuni, M., Natsume, T., Yoshida, K., Sugimoto, N., Kanemaki, M. T., & Fujita, M. (2019). Inhibiting the MCM8-9 complex selectively sensitizes cancer cells to cisplatin and olaparib. Cancer Science, 110(3), 1044-1053. https://doi.org/10.1111/cas.13941