Abstract
Despite being the leading cause of cancer death, targeted therapy for gastric cancer is yet to be established. Wnt/β-catenin signaling is highly deregulated in cancers of gastrointestinal origin including gastric cancers. Stabilization and deregulation of β-catenin occurs at multiple levels and so is being needed to identify a spectrum of Wnt inhibitors to combat deregulated Wnt signaling at the level of various targets and also in different combinations. We developed a luciferase reporter based gastric cancer cellular assay system for Wnt pathway modulator screening and identified nimesulide, a known COX-2 inhibitor as an inhibitor of Wnt/β catenin signaling pathway. Comprehensive signaling pathway profiling revealed that nimesulide could inhibit STAT3, IRF1 and RXR signaling apart from inhibiting Wnt/β-catenin-Myc-E2F signaling cascade. Nimesulide elicits a strong anti-proliferative effect by promoting cell cycle arrest in multiple gastric cancer cell lines. Inhibition of Wnt and STAT3 signaling are found to be COX-2 independent, while the inhibition of RXR and IRF1 pathways are due to the COX-2 inhibiting feature of nimesulide. While nimesulide is capable of activating Notch signaling in gastric cancer cells, celecoxib inhibits Wnt, Myc, E2F, RXR, STAT3, MAPK and Notch signaling pathways in gastric cancer cells. Signaling pathway focused analysis of gastric cancer transcriptome revealed that Wnt, STAT3, IRF1 and RXR signaling pathway are highly deregulated in majority of gastric tumors and indicates the potential of nimesulide and celecoxib class of drugs for targeted gastric cancer therapeutics. The differential inhibition of multiple signaling by nimesulide and celecoxib deserve further investigation.
Highlights
Stomach cancer is the second leading cause of global cancer mortality and estimated as fourth common cancer worldwide [1,2]
Wnt/β catenin signaling plays a predominant role in gastric tumorigenesis and the recent pathway focused investigation of gastric cancer transcriptome has shown the deregulation of Wnt/β-catenin signaling in 46 % of patients [4]
Apart from its own activation, increasing evidences show that Wnt signaling involves in molecular conversation with other oncogenic counterparts such as MAPK, PI3K/AKT, Signal Transducer and Activator of Transcription 3 (STAT3) and Hedgehog [9,10,11,12] and potentiates cancer growth
Summary
Stomach cancer is the second leading cause of global cancer mortality and estimated as fourth common cancer worldwide [1,2]. Wnt/β catenin signaling plays a predominant role in gastric tumorigenesis and the recent pathway focused investigation of gastric cancer transcriptome has shown the deregulation of Wnt/β-catenin signaling in 46 % of patients [4]. Several members of Wnt/β-catenin pathway like APC, CDH1, CTNNB1 and AXIN2 [5,6,7] are often mutated and being the primary causative factors which makes the β-catenin nonresponsive to APC/AXIN2/GSK-3β destruction complex. This results in cytosolic stabilization and nuclear accumulation of β-catenin and drives transcriptional activation of Wnt target genes [8].
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