Helicobacter pylori and Epstein Barr virus (EBV) are group1 carcinogens and their role in Gastric cancer (GC) is well established. Previously we have shown that H. pylori and EBV appears to support aggressive gastric oncogenesis through the upregulation of oncoprotein Gankyrin. Natural plant active molecules have the potential to interrupt oncogenesis. Herein, we investigated the potential of Withania somnifera root extract (WSE) as a possible chemotherapeutic agent against host oncoprotein Gankyrin whose expression was altered by H. pylori and EBV-associated modified cellular milieu. The results show that WSE does not have any inhibitory effect on H. pylori and EBV-associated gene transcripts except for the lmps (lmp1, lmp2a, and lmp2B). Moreover, the WSE exert their anticancer activity via host cellular response and decreased the expression of cell-migratory (mmp3 and mmp7); cell-cycle regulator (pcna); antiapoptotic gene (bcl2); increased the expression of the proapoptotic gene (apaf1 and bax); and tumor suppressor (p53, prb, and pten). Knockdown of Gankyrin followed by the treatment of WSE also decreases the expression of TNF-ɑ, Akt, and elevated the expression of NFkB, PARP, Casp3, and Casp9. WSE also reduces cell migration, and genomic instability and forced the cells to commit programmed cell death. Moreover, molecular simulation studies revealed that out of eight active compounds of WSE, only four compounds such as withaferin A (WFA), withanoside IV (WA4), withanolide B (WNB), and withanolide D (WND) showed direct stable interaction with Gankyrin. This article reports for the first time that treatment of WSE decreased the cancerous properties through host cellular response modulation in gastric epithelial cells coinfected with H. pylori and EBV.Communicated by Ramaswamy H. Sarma.
Keywords: Co-infection; EBV; Helicobacter pylori; cell signaling; gankyrin; withania somnifera.