Data from MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> <i>MUC1</i>, an oncogene overexpressed in multiple solid tumors, including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth-promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and <i>in vivo</i> models.</p><p><b>Experimental Design:</b> We used <i>MUC1</i>-knockdown and -overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through <i>in vitro</i> cytotoxicity, clonogenicity, DNA damage response, and metabolomic evaluations. We also investigated whether inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance by using <i>in vitro</i> and <i>in vivo</i> models.</p><p><b>Result</b>s: <i>MUC1</i> expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in <i>in vitro</i> models. Pretreatment with the glycolysis inhibitor 3-bromopyruvate abrogated MUC1-mediated radiation resistance both <i>in vitro</i> and <i>in vivo</i>, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pretreatment with nucleoside pools.</p><p><b>Conclusions:</b> MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation resistance in pancreatic cancer and targeted effectively through glycolytic inhibition. <i>Clin Cancer Res; 23(19); 5881–91. ©2017 AACR</i>.</p></div>