"Two hits - one stone"; increased efficacy of cisplatin-based therapies by targeting PCNA's role in both DNA repair and cellular signaling.

Autor:	Søgaard CK; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Blindheim A; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Department of Urology and Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Røst LM; Department of Biotechnology and Food Science, NTNU, Trondheim, Norway., Petrović V; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Nepal A; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Bachke S; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Liabakk NB; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Gederaas OA; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., Viset T; Department of Pathology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Arum CJ; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Department of Urology and Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Bruheim P; Department of Biotechnology and Food Science, NTNU, Trondheim, Norway., Otterlei M; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.; APIM Therapeutics A/S, Trondheim, Norway.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Aug 21; Vol. 9 (65), pp. 32448-32465. Date of Electronic Publication: 2018 Aug 21 (Print Publication: 2018).
DOI:	10.18632/oncotarget.25963
Abstrakt:	Low response rate and rapid development of resistance against commonly used chemotherapeutic regimes demand new multi-targeting anti-cancer strategies. In this study, we target the stress-related roles of the scaffold protein PCNA with a cell-penetrating peptide containing the PCNA-interacting motif APIM. The APIM-peptide increased the efficacy of cisplatin-based therapies in a muscle-invasive bladder cancer (MIBC) solid tumor model in rat and in bladder cancer (BC) cell lines. By combining multiple omics-levels, from gene expression to proteome/kinome and metabolome, we revealed a unique downregulation of the EGFR/ERBB2 and PI3K/Akt/mTOR pathways in the APIM-peptide-cisplatin combination treated cells. Additionally, the combination treatment reduced the expression of anti-apoptotic proteins and proteins involved in development of resistance to cisplatin. Concurrently, we observed increased levels of DNA breaks in combination treated cells, suggesting that the APIM-peptide impaired PCNA - DNA repair protein interactions and reduced the efficacy of repair. This was also seen in cisplatin-resistant cells, which notably was re-sensitized to cisplatin by the APIM-peptide. Our data indicate that the increased efficacy of cisplatin treatment is mediated both via downregulation of known oncogenic signaling pathways and inhibition of DNA repair/translesion synthesis (TLS), thus the APIM-peptide hits both nuclear and cytosolic functions of PCNA. The novel multi-targeting strategy of the APIM-peptide could potentially improve the efficacy of chemotherapeutic regiments for treatment of MIBC, and likely other solid tumors. Competing Interests: CONFLICTS OF INTEREST APIM Therapeutics is a spin-off company of the Norwegian University of Science and Technology, and has co-funded this study. Professor Marit Otterlei is an inventor, minority shareholder and CSO of this company. Patent application no: PCT/GB2009/000489 “New PCNA interacting motif”, filed on February 20, 2009. There are no further patents, products or development or marked products to declare. The other authors declare no conflict of interest.
Databáze:	MEDLINE
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