Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Xuehuo Zeng; Wilnelly Hernandez-Sanchez; Mengyuan Xu; Tawna L Whited; Diane Baus; Junran Zhang; Anthony J Berdis; Derek J Taylor

doi:10.1016/j.celrep.2018.05.020

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Cell Rep. 2018 Jun 5;23(10):3031-3041. doi: 10.1016/j.celrep.2018.05.020.

Authors

Xuehuo Zeng¹, Wilnelly Hernandez-Sanchez¹, Mengyuan Xu¹, Tawna L Whited¹, Diane Baus¹, Junran Zhang², Anthony J Berdis³, Derek J Taylor⁴

Affiliations

¹ Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
² Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH 44106, USA.
³ Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
⁴ Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: [email protected].

Abstract

Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2'-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy.

Keywords: 5-fluoro-2'-deoxyuridine; DNA damage; POT1; floxuridine; telomerase; telomere.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aminopeptidases / metabolism
Cell Death
Cell Line, Tumor
DNA / metabolism
DNA Damage
Deoxyuridine / analogs & derivatives
Deoxyuridine / metabolism
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
Gene Silencing
HEK293 Cells
Humans
Models, Biological
Neoplasms / enzymology*
Neoplasms / pathology*
Nuclear Proteins / metabolism
Nucleosides / administration & dosage*
Protein Binding
Pyrimidines / metabolism
RNA, Small Interfering / metabolism
Serine Proteases / metabolism
Shelterin Complex
Telomerase / metabolism*
Telomere / metabolism
Telomere-Binding Proteins / metabolism
Thymidine / metabolism
Tripeptidyl-Peptidase 1

Substances

Nuclear Proteins
Nucleosides
POT1 protein, human
Pyrimidines
RNA, Small Interfering
Shelterin Complex
Telomere-Binding Proteins
Tripeptidyl-Peptidase 1
5-formyl-2'-deoxyuridine
DNA
Telomerase
Serine Proteases
Aminopeptidases
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
pyrimidine
Thymidine
Deoxyuridine

Abstract

Publication types

MeSH terms

Substances

Grants and funding