Inhibition of GSK-3beta enhances reovirus-induced apoptosis in colon cancer cells.
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 beta-catenin. Thus, it is possible that enhanced beta-catenin may augment reoviral susceptibility in colon cancer cells. To explore this hypothesis, HEK293 cells were treated with the glycogen synthase kinase (GSK)-3beta inhibitor LiCl, thereby inducing beta-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 beta-catenin does not enhance the replication of reovirus. Instead, we observed that inhibition of GSK-3beta with LiCl decreased reovirus-induced NF-kappaB 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-3beta inhibitor, AR-A014418. Finally, we identified that inhibition of NF-kappaB sensitized apoptosis of HEK293 or HCT 116 cells during reovirus infection. Taken together, we propose that inhibition of GSK-3beta sensitizes reovirus-induced apoptosis of colon cancer cells by down-regulation of NF-kappaB activity, offering a potentially improved therapeutic strategy for the treatment of colon cancer.
Min
Hye-Jin
HJ
Department of Nanomedical Engineering, BK21 Nanofusion Technology Team, Pusan National University, Miryang, Gyeongnam, Korea.
Koh
Sang Seok
SS
Cho
Il-Rae
IR
Srisuttee
Ratakorn
R
Park
Eun-Hee
EH
Jhun
Byung Hak
BH
Kim
Yong-Gyun
YG
Oh
Sangtaek
S
Kwak
Ju Eun
JE
Johnston
Randal N
RN
Chung
Young-Hwa
YH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000628:therapy / Q000821:virology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D030102:Orthoreovirus, Mammalian / Q000502:physiology; D012088:Reoviridae Infections / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3