Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive of solid malignancies responsible for around 330,000 deaths globally and accounts for the fourth most common cause of deaths due to cancer in USA. There has been a little advancement in the treatment of PDAC patients and the mortality rate has remained unchanged and may even be climbing up. Metformin, an oral biguanide medication used to treat type-2 diabetes mellitus, has demonstrated potential therapeutic effect against PDAC. Recent meta-analysis and epidemiologic studies indicate that diabetic patients treated with metformin were less likely to develop pancreatic cancer exhibit longer overall survival than those using other oral antidiabetic medications. Although there are several reports of the possible mode of action of Metformin against PDAC, no direct cellular/ molecular target is till reported.
The present study aims to identify the direct molecular target of metformin in pancreatic cancer cells. Previously, we have demonstrated that matricellular protein CCN1/ Cyr61 plays pivotal role in pancreatic cancer development, maintenance of stemness, and induction of tumor angiogenesis. Hence the goal of this study is to investigate whether CCN1/ Cyr61 signaling cascade acts as a potential target for metformin. The encouraging results we have obtained so far reveal that metformin, which reduces CCN1 expression, significantly inhibits SDF-1 induced invasion, formation of tumor spheres (pancospheres) and also results in the down regulation of CXCR4 receptor in PC cell lines (Panc-1 and AsPC-1). Interestingly we observed that CXCR4 expression is drastically down regulated in genetically engineered CCN1-knock out Panc-1 (Panc-1 KO CCN1) cells, compared to the scrambled shRNA transfected Panc-1 cells. Further, it is also observed that Panc-1 K. CCN1 cells are found to be more susceptible to metformin treatment, whereas extracellular supplementation of recombinant CCN1 protein significantly abrogates the effect of metformin on PC cells. Moreover, tumor progression was found to be drastically inhibited in metformin treated Panc-1 (CCN1+ve) tumor xenografts in nude mice model, while the anti-tumorigenic effect of metformin was found to be more drastic in Panc-1 KO CCN1 tumor xenografts. In this scenario, we conclude that CCN1 acts as a direct target for metformin in PC cells, and targeted knock down of CCN1 increases the effectiveness of metformin.
[This project is funded by VA Merit Award grants (SB & SKB)]
Citation Format: Amlan Das, Archana De, Inamul Haque, Gargi Maity, Sushanta Banerjee, Snigdha Banerjee. Metformin inhibits the oncogenic potential and invasiveness of pancreatic cancer cells targeting CCN1-CXCR4 axis : A new perspective for an old antidiabetic drug. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3572. doi:10.1158/1538-7445.AM2015-3572