Open AccessInhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib
Author(s) -
Morii Issay,
Iwabuchi Yukiko,
Mori Sumiko,
Suekuni Masaki,
Natsume Toyoaki,
Yoshida Kazumasa,
Sugimoto Nozomi,
Kanemaki Masato T.,
Fujita Masatoshi
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13941
Subject(s) - olaparib , cisplatin , cancer research , poly adp ribose polymerase , cancer cell , dna damage , dna repair , chemistry , rad51 , microbiology and biotechnology , biology , cancer , polymerase , biochemistry , dna , genetics , chemotherapy
MCM 8 and MCM 9 are paralogues of the MCM 2‐7 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 MCM 9 or knockdown of MCM 8 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 MCM 8, providing a rationale for cancer‐specific hypersensitization to cisplatin and olaparib. Finally, we showed that knocking out MCM 9 increased the sensitivity of HCT 116 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.