Inhibition of GSK-3β enhances reovirus-induced apoptosis in colon cancer cells

Abstract

Abstract. Reovirus functions as an oncolytic agent for many types of cancer including colon cancer. Although most studies have emphasized the role of activated Ras signaling in enhancing reoviral oncolysis in susceptible cells, we note that many colon cancers also display elevated ß-catenin. Thus, it is possible that enhanced ß-catenin may augment reoviral susceptibility in colon cancer cells. To explore this hypothesis, HEK293 cells were treated with the glycogen synthase kinase (GSK)-3ß inhibitor LiCl, thereby inducing ß-catenin, followed by reoviral infection. Co-administration with LiCl indeed enhanced cell death compared to reovirus infection alone, but this was not associated with elevated reoviral replication. Similarly, HEK293 cells expressing the Frizzled-1 receptor in Wnt3a-conditioned medium also showed reovirus replication equivalent to that in cells in control medium, further suggesting that up-regulation of ß-catenin does not enhance the replication of reovirus. Instead, we observed that inhibition of GSK-3ß with LiCl decreased reovirus-induced NF-κB activation, leading to accelerated apoptosis via caspase 8 activation. We further found that colon cancer HCT116 cells were sensitized to apoptosis by co-treatment with reovirus and a GSK-3ß inhibitor, AR-A014418. Finally, we identified that inhibition of NF-κB sensitized apoptosis of HEK293 or HCT 116 cells during reovirus infection. Taken together, we propose that inhibition of GSK-3ß sensitizes reovirus-induced apoptosis of colon cancer cells by downregulation of NF-κB activity, offering a potentially improved therapeutic strategy for the treatment of colon cancer.

The mechanism of apoptosis in human acute promyelocytic leukemia cells treated with sorafenib and lithium chloride

“…The effect of GSK-3β was thought to be independent of NF-κB [39]. Other authors found that inhibition of GSK-3β by LiCl reduced NF-κB activation, which accelerated caspase 8-mediated apoptosis [40]. In a study on colorectal cancer cells, it was reported that LiCl treatment reduced NF-κB levels and stimulated apoptosis in cells by affecting the B-cell lymphoma gene and other surviving genes [15].…”