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

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 if inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance 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. Pre-treatment with the glycolysis inhibitor, 3-bromopyruvate (BrPA) 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 pre-treatment 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.

Metabolic Alterations in Pancreatic Cancer Progression

“…Cancer cells undergo metabolic reprogramming to adapt to the proliferative demands and stressful microenvironments by increasing the uptake of nutrients and their incorporation in the biosynthetic pathways [22,33,34]. The Warburg effect represents metabolic adaptations in proliferating cells and cancer cells where increased glucose uptake, despite the presence of oxygen, sustains anabolic pathways that culminate into biomass production.…”

“…Subsequently, it has been shown that cancer cells reroute glucose and other nutrients into anabolic pathways to provide building blocks essential for cell division [20]. Multiple oncogenes and signaling pathways, beyond Kras and p53, have since been demonstrated to regulate metabolic reprogramming and contribute to poor therapy response [20][21][22][23][24]. As metabolic reprogramming plays a pivotal role in cancer initiation, progression, and therapy responsiveness, different diagnostic techniques based on metabolism are routinely utilized in the clinic.…”

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

“…The efficacy of several cancer therapeutics is linked to their effect on metabolic alterations in tumor cells (4–6). Hence, combining strategies to target metabolism along with the current standard of care will prevent resistance to the therapeutics and may kill the tumor cells more effectively.…”

Analysis of exosomal circRNAs upon irradiation in pancreatic cancer cell repopulation

“…These GO terms might be associated with nucleotide metabolism, which was involved in radiotherapy [29] . Refer to MF, "Binding", "protein methyltransferase activity", "histone methyltransferase activity", "histone methyltransferase activity (H3-K4 speci c)" and "histone-lysine N-methyltransferase activity" were highly enriched.…”