MUC1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer

Venugopal Gunda, Joshua Souchek, Jaime Abrego, Surendra K. Shukla, Gennifer D. Goode, Enza Vernucci, Aneesha Dasgupta, Nina V. Chaika, Ryan J. King, Sicong Li, Shuo Wang, Fang Yu, Tadayoshi Bessho, Chi Lin, Pankaj K. Singh

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Purpose: MUC1, 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 in vivo models. Experimental Design: We used MUC1-knockdown and -overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro 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 in vitro and in vivo models. Results: MUC1 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 in vitro models. Pretreatment with the glycolysis inhibitor 3-bromo-pyruvate abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pretreatment with nucleoside pools. Conclusions: MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation resistance in pancreatic cancer and targeted effectively through glycolytic inhibition.

Original languageEnglish (US)
Pages (from-to)5881-5891
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number19
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gunda, V., Souchek, J., Abrego, J., Shukla, S. K., Goode, G. D., Vernucci, E., Dasgupta, A., Chaika, N. V., King, R. J., Li, S., Wang, S., Yu, F., Bessho, T., Lin, C., & Singh, P. K. (2017). MUC1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer. Clinical Cancer Research, 23(19), 5881-5891. https://doi.org/10.1158/1078-0432.CCR-17-1151