Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer.

Autor: Gomes-Filho SM; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil., Dos Santos EO; Instituto Butantã, São Paulo, SP, Brazil., Bertoldi ERM; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil., Scalabrini LC; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil., Heidrich V; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil., Dazzani B; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil., Levantini E; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Reis EM; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil., Bassères DS; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, Bloco 12 inferior, sala 1200, São Paulo, SP, 05508-000, Brazil. basseres@iq.usp.br.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2020 Jun; Vol. 43 (3), pp. 445-460. Date of Electronic Publication: 2020 Mar 19.
DOI: 10.1007/s13402-020-00498-5
Abstrakt: Purpose: Oncogenic KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs). As yet, however, no effective therapies are available for KRAS-induced malignancies. Therefore, research aimed at the identification of KRAS targets with therapeutic potential is warranted. Our goal was to investigate Aurora A (AURKA) and targeting protein for Xklp2 (TPX2) as potential therapeutic targets in PDAC.
Methods: AURKA and TPX2 expression was assessed using RNAseq and qRT-PCR in PDAC patient samples and matched non-tumor pancreatic tissues. Publicly available PDAC datasets were used to investigate associations of AURKA and TPX2 expression levels with patient survival and the presence of KRAS mutations. Next, we used an Aurora kinase inhibitor, or KRAS, AURKA and TPX2 targeting using RNA interference in KRAS-mutant PDAC cells and, subsequently, analyzed their clonogenic and anchorage-independent growth and migration.
Results: We found that relative to matched non-tumor tissues, PDAC tumors displayed significantly higher expression levels of AURKA and TPX2. In addition, we found that AURKA and TPX2 were co-expressed in PDAC datasets, and that high expression levels of AURKA and TPX2 were associated with a shorter patient survival and with the presence of oncogenic KRAS mutations. In addition, we found that siRNA-mediated KRAS targeting in KRAS-mutant PDAC cells reduced AURKA and TPX2 expression. Furthermore, targeting AURKA or TPX2 in KRAS-mutant PDAC cells reduced their clonogenic and anchorage-independent growth, as well their migration.
Conclusions: From our data we conclude that AURKA and TPX2 may act as KRAS biomarkers in PDAC that can predict a worse prognosis, and that AURKA or TPX2 targeting in PDAC cells may reduce their transformed phenotype. These results indicate that AURKA and TPX2 may serve as promising targets to be explored for KRAS-mutant PDAC therapy.
Databáze: MEDLINE
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