Molecular Targeting of Cancer-Associated PCNA Interactions in Pancreatic Ductal Adenocarcinoma Using a Cell-Penetrating Peptide

Shanna J Smith; Caroline M Li; Robert G Lingeman; Robert J Hickey; Yilun Liu; Linda H Malkas; Mustafa Raoof

doi:10.1016/j.omto.2020.03.025

Molecular Targeting of Cancer-Associated PCNA Interactions in Pancreatic Ductal Adenocarcinoma Using a Cell-Penetrating Peptide

Mol Ther Oncolytics. 2020 Apr 8:17:250-256. doi: 10.1016/j.omto.2020.03.025. eCollection 2020 Jun 26.

Authors

Shanna J Smith¹, Caroline M Li¹, Robert G Lingeman¹, Robert J Hickey², Yilun Liu³, Linda H Malkas¹, Mustafa Raoof⁴

Affiliations

¹ Department of Molecular and Cellular Biology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
² Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
³ Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁴ Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.

Abstract

Pancreatic ductal adenocarcinoma is a particularly difficult cancer to treat due to a lack of effective screening or treatment. Pancreatic cancer cells exhibit high proliferating cell nuclear antigen (PCNA) expression, which is associated with poor prognosis. PCNA, an important nuclear DNA replication and repair protein, regulates a myriad of proteins via the interdomain connector loop. Within this region, amino acids 126-133 are critical for PCNA interactions in cancer cells. Here, we investigate the ability of a decoy cell-penetrating peptide, R9-caPeptide, that mimics the interdomain connector loop region of PCNA to disrupt PCNA-protein interactions in pancreatic cancer cells. Our data suggest that R9-caPeptide causes dose-dependent toxicity in a panel of pancreatic cancer cell lines by inhibiting DNA replication fork progression and PCNA-regulated DNA repair, ultimately causing lethal DNA damage. Overall, these studies lay the foundation for novel therapeutic strategies that target PCNA in pancreatic cancer.

Keywords: Cell death; Cell-penetrating peptide; DNA damage; DNA damage response; DNA repair; PCNA; Pancreatic Cancer; Peptide therapeutics; Proliferating cell nuclear antigen; Replication Stress.

Abstract

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