“Two hits - one stone”; increased efficacy of cisplatin-based therapies by targeting PCNA’s role in both DNA repair and cellular signaling
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Caroline Krogh Søgaard1,3,*, Augun Blindheim1,2,*, Lisa M. Røst4, Voin Petrović1, Anala Nepal1, Siri Bachke1, Nina-Beate Liabakk1, Odrun A. Gederaas1, Trond Viset5, Carl-Jørgen Arum1,2, Per Bruheim4 and Marit Otterlei1,3,6
1Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
2Department of Urology and Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
3Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
4Department of Biotechnology and Food Science, NTNU, Trondheim, Norway
5Department of Pathology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
6APIM Therapeutics A/S, Trondheim, Norway
*These authors have contributed equally to this work
Marit Otterlei, email: [email protected]
Keywords: muscle-invasive bladder cancer; APIM-peptide; cellular signaling; DNA repair; cisplatin resistance
Received: June 06, 2018 Accepted: July 31, 2018 Published: August 21, 2018
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.
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