Abstract 2229: Galectin-1 reduces the efficacy of PI3K pathway inhibitors in glioblastoma cells
Authors: James D. Perry, Arnab Chakravarti, Tim Lautenschlaeger
Journal: Cancer Research (2012)

Abstract Galectin-1 (Gal-1), is a small ∼14kD carbohydrate binding protein that is known to be significantly upregulated in gliomas, and has also been closely associated with patient survival. PI3K/AKT signaling is important in cancer cells because upregulation of this pathway is associated with increased cell survival and growth. Specifically in glioblastomas there is a signaling alteration in the RTK/PI3K/RAS/PTEN axis in nearly 90% of patients leading to therapeutic resistance and poor prognosis. While Gal-1 has a defined role in activating MAPK signaling, the effect of Gal-1 on PI3K signaling is unclear. The purpose of these experiments was to study the role that Gal-1 has in cellular survival signaling, primarily the PI3K pathway. Previous experiments from our laboratory have demonstrated a significant role for Gal-1 in PI3K signaling and AKT activation. An in vitro PI3K reaction showed that Gal-1 can increase PI3K enzyme activity, even in the presence of a PI3K inhibitor. Gal-1 was also shown to specifically interact with the PI3K enzyme in an in vitro Co-IP assay. Based on these results, we investigated the role of Gal-1 in protecting cells from PI3K pathway inhibition. LN229, U87, and LN18 glioma cell lines were used for these experiments. Cells were treated with multiple different inhibitors for specific proteins in the PI3K signaling pathway (EGFR - Gefitinib, AKT - MK-2206, PI3K - LY294002 and PI-103, mTor - AZD 8055 and Everolimus). Initially, control cells were compared with cells of different Gal-1 status for PI3K pathway activation by western blot. We looked at multiple levels of activation including pAKT, p-mTOR, and p-p70S6K. Following this analysis, proliferation was examined by MTS assay and clonogenic survival was also tested. Our results indicate that in the absence of Gal-1, all of the different inhibitors listed above showed increased signaling inhibition in each of the cell lines tested. In the control cells, higher concentrations of these inhibitors were required to cause similar reduction in pathway activation markers such as pAKT. Based on these results we examined proliferation rates and clonogenic survival for several of the tested inhibitors. In these experiments, we observed that Gal-1 increases baseline survival signaling in cells and leads to an increased resistance to many of the tested inhibitors. In conclusion Gal-1 has demonstrated an ability to protect cancer cells from the effects of multiple PI3K pathway inhibitors (i.e. PI3K, EGFR, and mTOR). Likely, this effect is due to the increased baseline survival signaling seen in Gal-1 expressing cells. While the mechanism for Gal-1's affect on inhibitor activity is still under investigation, this research highlights that Gal-1 status might serve as a predictive biomarker for the effectiveness of many different PI3K pathway inhibitors that are currently showing limited efficacy in clinical trials. 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 2229. doi:1538-7445.AM2012-2229