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

Abstract

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.

Effects of dietary restriction on genome stability are sex and feeding regimen dependent

“…38 Like many other DNA-damaging agents, cisplatin not only kills cancer cells but also induces massive damage to normal cells. As strategies to treat cancer have focused primarily on the killing of cancer cells, we have previously found that several phytochemicals such as geraniin and the geraniin-containing herbal drug-Phyllanthus emblica-are able to protect normal but not cancer cells against spontaneous and chemotherapyinduced GIN, [50][51][52][53][54] suggesting a possibility that changes in diet could improve a chemotherapy drug's side effects on normal cells. Indeed, short term starvation has potential to protect normal cells against the cytotoxicity of high-dose chemotherapy 55,56 and multiple cycles of fasting augment the anticancer efficacy of certain chemotherapy drugs via synergistically promoting DNA breaks in cancer cells.…”

Non-Canonical Programmed Cell Death in Colon Cancer

“…The SAC (spindle assembly checkpoint) makes sure chromosomes segregate correctly to avoid MC, and the DNA structure checkpoint prevents DNA damage. There are drugs aiming at the SAC or DNA structure checkpoint to induce MC in colon cancer cells, including geraniin [ 30 ], docetaxel, and vincristine, which have a synergistic effect with Aurora inhibitor SNS-314 [ 31 ], a rimonabant that suppresses the progression of colon cancer [ 32 ] and low doses (~0.5 μM) of reversine [ 33 ].…”