Abstract 1978: Isorhamnetin modulates PPARδ activation pathway leading to the suppression of proliferation, invasion and induction of apoptosis in gastric cancer
Authors: Lalitha Ramachandran, Manu Kanjoormana Aryan, Chen Luxi, Li Feng, Peramaiyan Rajendran, Chun Wei Yap, Alan Prem Kumar, Gautam Sethi
Journal: Cancer Research (2012)

Abstract Background: Gastric cancer, including cancer of the esophago-gastric junction, is the fourth most common malignant tumor and the second-most common cause of cancer-related death. Though treatment options such as chemotherapy, radiotherapy and surgery are available, only a modest survival rate has been observed, with the most common complications being chemoresistance and tumor recurrence. Majority of gastric adenocarcinomas have been related to chronic inflammation induced by Helicobacter pylori infection. Peroxisome proliferator-activated receptors are ligand-activated intracellular transcription factors that have been shown to be involved in tumor growth. However, its role in gastric cancer remains unclear. In this study, we report the anticancer effects of Isorhamnetin (IH), a 3′-O-methylated metabolite of quercetin on gastric cancer cells, and its potential effect on the PPAR-γ activation pathway. Method: Various gastric cancer cell lines were used in the study. To investigate the effect of IH on gastric cancer cells, we used techniques such as cell proliferation assays, wound healing assay, matrigel invasion assay, western blot analysis, cell cycle analysis, real time PCR analyses and live and dead assay. Whether IH could modulate activation of PPAR-γ was also investigated by molecular docking analysis. Results: We found that IH exerted strong anti-proliferative effect in gastric cancer cells and, when combined with 5-fluorouracil and cisplatin, increased cytotoxicity. IH was found to increase sub-G1 accumulation and annexin-V positive staining, indicating apoptotic induction. In addition, IH activated caspases 8, 9 and 3 in a time-dependent manner. Migratory and invasive properties of gastric cancer cells were also reduced in the presence of IH. Interestingly, we report for the first time that IH was able to increase PPAR-γ activity and down-regulate the expression of the genes for Bcl-2, Bcl-xL and survivin in gastric cancer cells. More importantly, the increase in PPAR-γ activity was prevented in the presence of PPAR-γ specific inhibitor and PPAR-γ dominant negative plasmid, suggesting that IH may act as a ligand of PPAR-γ. Also, we observed using molecular docking analysis that IH indeed formed interactions with 7 polar residues and 6 non-polar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity. Conclusion: Taken together, our novel observations suggest that IH may have potential implication in gastric cancer prevention and treatment, and show for the first time that the anti-tumor effect of IH may also be mediated through modulation of the PPAR-γ activation pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1978. doi:1538-7445.AM2012-1978