Geraniin Differentially Modulates Chromosome Stability of Colon Cancer and Noncancerous Cells by Oppositely Regulating their Spindle Assembly Checkpoint

Geraniin has been reported to specifically induce apoptosis in multiple human cancers, but the underlying mechanism is poorly defined. The spindle assembly checkpoint (SAC) is a surveillance system to ensure high-fidelity chromosome segregation during mitosis. Weakening of SAC to enhance chromosome instability (CIN) can be therapeutic because very high levels of CIN are lethal. In this study, we have investigated the effects of geraniin on the SAC of colorectal cancer HCT116 cells and noncancerous colon epithelial CCD841 cells. We find that treatment of HCT116 cells with geraniin leads to dose-dependent decrease of cell proliferation, colony formation, and anchorage-independent growth. Geraniin is found to induce apoptosis in mitotic and postmitotic HCT116 cells. Furthermore, geraniin weakens the SAC function of HCT116 cells by decreasing the transcriptional expression of several SAC kinases (particularly Mad2 and Bub1), which in turn leads to premature anaphase entry, mitotic aberrations, and CIN in HCT116 cells. In contrast, the proliferation of CCD841 cells is slightly inhibited by geraniin. Even more interestingly, geraniin increases the transcriptional expression of several SAC kinases (e.g., Mad1 and BubR1) to strengthen SAC efficiency, which contributes to the reduction of mitotic aberrations and CIN in CCD841 cells. Altogether, our findings reveal that the SAC pathway in human colon cancer and noncancerous cell lineages responses oppositely to geraniin treatment, resulting CIN promotion and suppression, respectively. Specific abrogation of SAC to induce catastrophic CIN in HCT116 cells may account for the selective anticancer action of geraniin.. Environ. Mol. Mutagen. 60:254-268, 2019. © 2018 Wiley Periodicals, Inc.