Proteomics

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APIM-peptide targeting PCNA improves cisplatin therapy in a rat muscle-invasive bladder cancer model


ABSTRACT: High mortality rate of muscle-invasive bladder cancer (MIBC) and complexity of disease demand new multi-targeting treatment strategies. Targeting proliferating cell nuclear antigen (PCNA) with a peptide containing the AlkB homologue 2 PCNA interacting motif (APIM), is shown to impair multiple vital cellular stress responses and induce hypersensitivity against several chemotherapeutics in different pre-clinical models. This study examine the anti-cancer efficacy of the novel APIM-peptide drug when combined with cisplatin-based therapies (cisplatin, cisplatin/gemcitabine (GC) and methotrexate/vinblastine/adriamycin/cisplatin (MVAC)) in a panel of bladder cancer (BC) cells and with intravenous cisplatin-therapy in a rat MIBC-model. Furthermore, we explore the molecular mechanisms underlying the observed effects on a genomic, proteomic and metabolomic level using microarray, multiplexed inhibitor bead (MIB)-assay, and targeted mass spectrometric metabolite profiling. The APIM-peptide significantly increased the efficacy of all cisplatin-based therapies in all BC cell lines tested, including a cisplatin resistant cell line and reduced the tumor load in cisplatin treated MIBC-bearing rats. Genome and proteome analysis of APIM-peptide/cisplatin treated BC cells revealed reduced expression of multiple proteins frequently overexpressed in MIBC. Of notice, the EGFR/ERBB2, PI3K/Akt and MAPK signaling pathways and anti-apoptosis were downregulated. We suggest that the anti-cancer effect of the APIM-peptide is through the downregulation of several known oncogenic signaling pathways including anti-apoptosis. Together our results indicate that the APIM-peptide represents a potential improved treatment approach for patients with MIBC.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Early Embryonic Cell, Kidney

DISEASE(S): Urinary System Benign Neoplasm

SUBMITTER: Animesh Sharma  

LAB HEAD: Marit Otterlei

PROVIDER: PXD008724 | Pride | 2018-09-10

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20150130_Voin_T4A.raw Raw
20150130_Voin_T4B.raw Raw
20150130_Voin_T4C.raw Raw
20150130_Voin_T4D.raw Raw
20150130_Voin_T5A.raw Raw
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Publications

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

Søgaard Caroline Krogh CK   Blindheim Augun A   Røst Lisa M LM   Petrović Voin V   Nepal Anala A   Bachke Siri S   Liabakk Nina-Beate NB   Gederaas Odrun A OA   Viset Trond T   Arum Carl-Jørgen CJ   Bruheim Per P   Otterlei Marit M  

Oncotarget 20180821 65


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 mult  ...[more]

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