Oncotarget

Research Papers:

Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells

Katrina M. Burchett, Asserewou Etekpo, Surinder K. Batra, Ying Yan, Michel M. Ouellette _

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Oncotarget. 2017; 8:83754-83767. https://doi.org/10.18632/oncotarget.19410

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Abstract

Katrina M. Burchett1, Asserewou Etekpo2, Surinder K. Batra3, Ying Yan3,4 and Michel M. Ouellette3,5

1Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA

2Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE, USA

3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

4Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA

5Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

Correspondence to:

Michel M. Ouellette, email: mouellet@unmc.edu

Keywords: pancreatic cancer, telomerase, telomere, imetelstat, poly(ADP-ribose) polymerase

Received: February 14, 2017     Accepted: July 12, 2017     Published: July 20, 2017

ABSTRACT

Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres. In AsPC1 cells, telomere attrition eventually led to the induction of crisis and the loss of the treated population. In L3.6pl cells, crisis was transient and followed by the emergence of GRN163L-resistant cells, which could grow at increasing concentrations of GRN163L. The Shelterin complex is a telomere-associated complex that limits the access of telomerase to telomeres. The telomerase inhibitory function of this complex can be enhanced by drugs that block the poly(ADP-ribosyl)ation of its TRF1 and/or TRF2 subunits. Combined treatment of the GRN163L-resistant L3.6pl cells with GRN163L and 3-aminobenzamide (3AB), a general inhibitor of poly(ADP-ribose) polymerases, led to additional telomere shortening and limited the lifespan of the resistant cells. Results from this work suggest that inhibitors of telomerase and poly(ADP-ribose) polymerases can cooperate to limit the lifespan of pancreatic cancer cells.


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