Abstract
Glycogen synthase kinase (GSK) 3β, which mediates fundamental cellular signaling pathways, has emerged as a potential therapeutic target for many types of cancer including colorectal cancer (CRC). During mitosis, GSK3β localizes in mitotic spindles and centrosomes, however its function is largely unknown. We previously demonstrated that translocated promoter region (TPR, a nuclear pore component) and dynein (a molecular motor) cooperatively contribute to mitotic spindle formation. Such knowledge encouraged us to investigate putative functional interactions among GSK3β, TPR, and dynein in the mitotic machinery of CRC cells. Here, we show that inhibition of GSK3β attenuated proliferation, induced cell cycle arrest at G2/M phase, and increased apoptosis of CRC cells. Morphologically, GSK3β inhibition disrupted chromosome segregation, mitotic spindle assembly, and centrosome maturation during mitosis, ultimately resulting in mitotic cell death. These changes in CRC cells were associated with decreased expression of TPR and dynein, as well as disruption of their functional colocalization with GSK3β in mitotic spindles and centrosomes. Clinically, we showed that TPR expression was increased in CRC databases and primary tumors of CRC patients. Furthermore, TPR expression in SW480 cells xenografted into mice was reduced following treatment with GSK3β inhibitors. Together, these results indicate that GSK3β sustains steady mitotic processes for proliferation of CRC cells via interaction with TPR and dynein, thereby suggesting that the therapeutic effect of GSK3β inhibition depends on induction of mitotic catastrophe in CRC cells.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide, causing over 600,000 deaths per year despite recently declining rates for incidence and mortality [1, 2]
To ascertain the role of Glycogen synthase kinase-3β (GSK3β) in tumor cell biology, we examined the effect of GSK3β inhibition on survival and proliferation of colorectal cancer (CRC) cells
Consistent with our previous studies [12,13,14,15], GSK3β-specific small-molecule inhibitors AR-A014418 [46] and SB-216763 [47] reduced the proliferation of CRC cells (HCT116, SW480, LoVo, and HT-29) compared with the same cells treated with dimethyl sulfoxide (DMSO, diluent for inhibitors) (Supplementary Figure 2A)
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide, causing over 600,000 deaths per year despite recently declining rates for incidence and mortality [1, 2]. Identification of new therapeutic targets is required to decrease CRC-related mortality. Roles for GSK3β and microRNAs in epithelial–mesenchymal transition and cancer stem cells were reported recently [10]. Our previous studies found that increased expression of total GSK3β and its active fraction (pGSK3βY216) is a distinct feature of many cancer types [reviewed in 7, 9, 11] including CRC [12,13,14,15]. We and other groups have demonstrated the preferential therapeutic effect of GSK3β inhibition against these cancers, underscoring this kinase as a promising target in cancer treatment [7,8,9]
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