Abstract
Chemotherapy and radiation in addition to surgery has proven useful in a number of different cancer types, but the effectiveness in normal tissue cannot be avoided in these therapies. To improve the effectiveness of these therapies selectively in cancer tissue is important for avoiding side effects. Early mitotic inhibitor 1 (Emi1) is known to have the function to inhibit anaphase-promoting complex/cyclosome ubiquitin ligase complex, which ubiquitylates the cell cycle-related proteins. It recently has been shown that Emi1 knockdown prevents transition from S to G2 phase by down-regulating geminin via anaphase-promoting complex/cyclosome activation. At present, anticancer drugs for targeting DNA synthesis to interfere with rapidly dividing cells commonly are used. As Emi1 depletion interferes with completion of DNA synthesis in cancer cells, we thought that Emi1 knockdown might enhance the sensitivity for anticancer agents. Here, we confirmed that Emi1 siRNA induced polyploidy for preventing transition from S to G2 phase in several cancer cell lines. Then, we treated Emi1 depleted cells with doxorubicin. Interestingly, increased apoptotic cells were observed after doxorubicin treatment in Emi1 siRNA-treated cancer cells. In addition, Emi1 depletion enhanced the sensitivity of x-ray irradiation in cancer cells. Importantly, synergistic effect of Emi1 knockdown in these combination therapies was not observed in normal cells. These results suggest that Emi1 siRNA can be a useful tool for enhancing of sensitivity of cancer cells to anticancer reagents and radiation.
Highlights
To improve the effectiveness of chemo- and radiotherapy only in cancer tissue is important for avoiding side effects
These results suggest that Early mitotic inhibitor 1 (Emi1) siRNA can be a useful tool for enhancing of sensitivity of cancer cells to anticancer reagents and radiation
We found that Emi1 knockdown inhibited cell proliferation through induction of rereplication and enhanced the sensitivity of anticancer reagents and x-ray-treated cancer cells, but normal cells were not sensitized with Emi1 depletion
Summary
To improve the effectiveness of chemo- and radiotherapy only in cancer tissue is important for avoiding side effects. As Emi depletion interferes with completion of DNA synthesis in cancer cells, we thought that Emi knockdown might enhance the sensitivity for anticancer agents. Synergistic effect of Emi knockdown in these combination therapies was not observed in normal cells These results suggest that Emi siRNA can be a useful tool for enhancing of sensitivity of cancer cells to anticancer reagents and radiation. Ionizing radiation works by damaging DNA to control tumor cell growth/division, but the effect of radiation in normal tissues cannot be avoided in these therapies. As Emi depletion interferes with completion of DNA synthesis in cancer cells [18, 19], we speculated that inhibition of Emi in cancer cells might enhance the sensitivity of anticancer agents. We examined the combined effects by one of the major anticancer agents, doxorubicin, and Emi depletion in various tumor cells
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