Abstract
Although MASTL (microtubule-associated serine/threonine kinase-like) is an attractive target for anticancer treatment, MASTL inhibitors with antitumor activity have not yet been reported. In this study, we have presented a novel MASTL inhibitor, MKI-1, identified through in silico screening and in vitro analysis. Our data revealed that MKI-1 exerted antitumor and radiosensitizer activities in in vitro and in vivo models of breast cancer. The mechanism of action of MKI-1 occurred through an increase in PP2A activity, which subsequently decreased the c-Myc protein content in breast cancer cells. Moreover, the activity of MKI-1 in the regulation of MASTL-PP2A was validated in a mouse oocyte model. Our results have demonstrated a new small-molecule inhibitor of MASTL, MKI-1, which exerts antitumor and radiosensitizer activities through PP2A activation in breast cancer in vitro and in vivo.
Highlights
Mitosis is considered an attractive target for selective anticancer treatment owing to the dysregulation of mitotic kinases and checkpoints in cancerous cells compared with those in normal cells [1, 2]
As Microtubule-associated serine/threonine kinase-like (MASTL) is a candidate target for radiosensitization in nonsmall cell lung cancer cells [19] and MASTL depletion inhibits the radioresistant breast cancer stem cells (BCSCs) through caspase-2 activation, which is a major caspase in the mitotic catastrophe in response to DNA damage [14], we examined the effects of MKI-1 on the radiosensitivity of breast cancer cells
Recent studies suggested MASTL was an attractive target for anticancer treatment owing to its regulation of various oncogenic properties, including cellular transformation, metastasis, chromosomal instability, and the DNA damage response (11, FIGURE 6 | MKI-1 reduced c-Myc stability through PP2A activation in MCF7 cells. (A,C,D) MCF7 cells transfected with either control siRNA, MASTL siRNA, B55α siRNA, B55δ siRNA, or B56α siRNA for 36 h. (B) MCF7 cells were treated with DMSO (Ctrl), 40 μM forskolin, 20 μM MKI-1, 50 nM Okadaic acid (OA), or 50 nM OA with 20 μM MKI-1 for 16 h
Summary
Mitosis is considered an attractive target for selective anticancer treatment owing to the dysregulation of mitotic kinases and checkpoints in cancerous cells compared with those in normal cells [1, 2]. Many mitotic kinases, including CDKs, AURKs, and PLK1, are associated with tumor progression and prognosis in many types of cancers [1, 2]; small molecule inhibitors for mitotic kinases have been developed as anticancer drugs [1, 2]. Inhibitors against these mitotic kinases have produced disappointing clinical results, with poor therapeutic effects due to their cytotoxicity to healthy cells [1]. Factors regulating both mitosis and mitotic checkpoints, which are overexpressed in cancer cells, are promising targets for selective anticancer treatment.
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