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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-bromopyruvate 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.

Author information​

Gunda V1, Souchek J1, Abrego J1, Shukla SK1, Goode GD1, Vernucci E1, Dasgupta A2, Chaika NV1, King RJ1, Li S3, Wang S3, Yu F4, Bessho T1, Lin C3, Singh PK5,4,6,7.

1 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.

2 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.

3 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.

4 Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska.

5 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. pankaj.singh@unmc.edu.

6 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.

7 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.