Alison L Halpern1,2, Patrick D Kohtz3, Allana M White3, Anna K Houk3, Jacob F Rehring3, Levent Hanson3, Martin D McCarter4, Molishree Joshi5, Xianzhong Meng3, David A Fullerton3, Michael J Weyant3. 1. Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, 1665 Aurora Court, Aurora, CO, 80045, USA. Alison.halpern@cuanschutz.edu. 2. University of Colorado, 12631 E. 17th Ave., C302, Aurora, CO, 80045, USA. Alison.halpern@cuanschutz.edu. 3. Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, 1665 Aurora Court, Aurora, CO, 80045, USA. 4. Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, 1665 Aurora Court, Aurora, CO, 80045, USA. 5. University of Colorado Anschutz Medical Campus Functional Genomics Core Facility, 12800 E 19th Street, RC1 North, P18-6222/6223, Aurora, CO, 80045, USA.
Abstract
BACKGROUND: Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling. AIMS: We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC. METHODS: Normal human esophageal epithelium, Barrett's esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers. RESULTS: sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls. CONCLUSIONS: sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition's ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.
BACKGROUND: Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling. AIMS: We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC. METHODS: Normal human esophageal epithelium, Barrett's esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers. RESULTS:sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls. CONCLUSIONS:sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition's ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.
Authors: John D Bradley; Alexei A Dmitrienko; Alan J Kivitz; Oscar S Gluck; Arthur L Weaver; Craig Wiesenhutter; Stephen L Myers; Gregory D Sides Journal: J Rheumatol Date: 2005-03 Impact factor: 4.666
Authors: Miral R Sadaria; Jessica A Yu; Xianzhong Meng; David A Fullerton; T Brett Reece; Michael J Weyant Journal: Anticancer Res Date: 2013-04 Impact factor: 2.480