Abstract 1172: (R,R’)-4′-Methoxy-1-naphthylfenoterol decreases glycolytic activity in the PANC-1 pancreatic cancer cell line

Abstract

Abstract We have recently demonstrated that (R,R’)-4′-methoxy-1-naphthylfenoterol (MNF) significantly reduces proliferation in pancreatic cancer (PancCA) cell lines, including PANC-1. MNF is a potent competitive inhibitor of the G-protein coupled receptor GPR55 and the anti-proliferative effects in PANC-1 cells was associated with down-stream events including attenuation of epidermal growth factor receptor (EGFR) expression and reduced phosphorylation of extracellular signal-related kinases [1]. In the current study, a previously described untargeted metabolomics approach using one-dimensional proton nuclear magnetic resonance (1D 1H NMR) [2] was used to examine the effect of MNF incubation (1 μM, 1h) on the intracellular metabolome of PANC-1 cells. Principal component analysis showed that MNF incubation produced a significantly different metabolome as compared to untreated cells. MNF treatment significantly reduced the signal associated with lactate indicating impaired glycolysis. Enhanced aerobic glycolysis in tumor cells, known as “the Warburg effect”, is a major metabolic contributor to cancer cell proliferation including PancCA [3]. Treatment of PANC-1 cells with the glycolysis inhibitor 3-bromopyruvate lowers cellular survival [4] and co-incubation of 3-bromopyruvate with the HSP90 inhibitor geldanamycin has a positive synergistic anticancer effect in vitro and in vivo [5]. Here, we showed metabolomics data that indicated also an increase in the relative expression of 3-hydroxybutyrate in response to MNF. Supplementation with ketone bodies such as 3-hydroxybutyrate has been associated with decreased proliferation and viability of PancCA cells in vitro and in vivo as well as tumor-related cachexia [1]. The signals associated with leucine, lysine, glycine and carnitine were also significantly upregulated with MNF treatment, indicating a possible role of fatty acid metabolism in MNF signaling. The data suggest that in addition to attenuating EGFR expression and reducing phosphorylation of extracellular signal-related kinases, MNF may affect PANC-1 cell proliferation and survival by disrupting glycolysis. Ref: 1. Paul RK, et.al. (R,R’)-4′-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility. Biochem Pharmacol. 2014;87(4):547-61. 2. Shukla SK, et.al. Metabolic Reprogramming Induced by Ketone Bodies Diminishes Pancreatic Cancer Cachexia. Cancer Metab. 2014;2:18. 3. Warburg, O. On the origin of cancer cells. Science. 1956;123:309-14. 4. Bhardwaj V, et.al. Glycolytic enzyme inhibitors affect pancreatic cancer survival by modulating its signaling and energetics. Anticancer Res. 2010;30:743-9. 5. Cao X, et.al. 2008. Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor. Clin Cancer Res.14:1831-9. Citation Format: Nagendra S. Singh, Jonathan Catazaro, Michel Bernier, Robert Powers, Irving Wainer. (R,R’)-4′-Methoxy-1-naphthylfenoterol decreases glycolytic activity in the PANC-1 pancreatic cancer cell line. [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 1172. doi:10.1158/1538-7445.AM2015-1172