Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation

Abstract

Abstract. The tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirusmediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the cotreatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells. IntroductionTNF-related apoptosis-inducing ligand (TRAIL), which belongs to the family of TNF, induces apoptosis in a wide variety of tumor cells in vitro and in vivo but does not cause toxicity in a majority of normal cells (1,2). Thus, TRAIL has been suggested as a novel anti-cancer therapeutic drug. The TRAIL-mediated apoptotic signal is transduced through the cell surface death receptor (DR)s such as DR4/TRAIL-R1 and DR5/TRAIL-R2 (3,4). Detailed studies have shown that TRAIL triggers apoptosis by recruiting the initiator procaspase-8 through the adaptor protein FADD. Caspase-8 can directly activate downstream effector caspases including procaspase-3, -6 and -7, or cleave Bid, which triggers mitochondrial damage (5,6). However, different types of cancer cells appear to differ in their sensitivity to TRAIL treatment. Recent studies have reported that prostate and renal cancer cells are resistant to TRAIL treatment due to an up-regulation of Akt activity and enhanced FLIP expression (7,8). In addition, it has been reported that the resistance of certain gastric cancer cells to TRAIL-induced apoptosis can be explained by the up-regulation of FLIPs by Akt, indicating that Akt is a crucial component in the regulation of TRAIL-induced apoptosis (9). In contrast, other studies failed to demonstrate a link between FLIP expression and TRAIL resistance using melanoma and Burkitt's lymphoma (10,11).The human reovirus is a ubiquitous, non-enveloped virus with 10 segments of double-stranded RNA (12). The virus infection is usually restricted to the upper respiratory and gastrointestinal tracts and is often...

Chimeric Antigen Receptor-T Cell and Oncolytic Viral Therapies for Gastric Cancer and Peritoneal Carcinomatosis of Gastric Origin: Path to Improving Combination Strategies

“…The mean volume of ascites and total number and weight of peritoneal tumors also decreased in reovirus-treated mice (Table 3). Meanwhile, Cho et al showed that reovirus downregulates the activation of Akt, a protein kinase that drives oncogenesis, and signaling molecules that promote cell proliferation and survival, including Ras and ERK (Table 3) [130]. Reovirus induced the apoptosis of TRAIL-resistant GC cells via these mechanisms.…”

Mammalian orthoreovirus infection in human epidermal growth factor receptor 2 positive (HER2+) breast cancer cells

“…The exact mechanism of MRV reduction in HIF-1 accumulation is not known. However, MRV inhibits the accumulation of HIF-1 independently of the oxygen-dependent pathway in a manner dependent on RACK1 and ubiquitin-mediated proteasomal degradation [32,37]. Moreover, a step between viral capsid cleavage and transcription of viral mRNA during the MRV life cycle has been found to be sufficient to induce the MRV effect on HIF-1 accumulation [34].…”

Activated Ras Signaling Pathways and Reovirus Oncolysis: An Update on the Mechanism of Preferential Reovirus Replication in Cancer Cells

“…Apoptosis by reovirus appears to require IRF-3 and NF-κB, in part, for efficient expression of the pro-apoptotic member of the Bcl-2 family, Noxa, independent of IFN-β induction (34). Reovirus appears to downregulate cellular FLICE inhibitory protein (cFLIP) and Akt activation to increase susceptibility to TRAIL-induced apoptosis in ovarian cancer cells and gastric cancer cells, respectively (59, 60). In neurons, reovirus-induced apoptosis is facilitated by upregulation of death-associated protein 6 (Daxx), an adaptor between the Fas death receptor and JNK signaling cascade, within the cytoplasm (61, 62).…”