RT Journal Article
T1 Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.
A1 Rubio, Carolina
A1 Avendaño-Ortiz, José
A1 Ruiz-Palomares, Raquel
A1 Karaivanova, Viktoriya
A1 Alberquilla, Omaira
A1 Sánchez-Domínguez, Rebeca
A1 Casalvilla-Dueñas, José Carlos
A1 Montalbán-Hernández, Karla
A1 Lodewijk, Iris
A1 Rodríguez-Izquierdo, Marta
A1 Munera-Maravilla, Ester
A1 Nunes, Sandra P
A1 Suárez-Cabrera, Cristian
A1 Pérez-Crespo, Miriam
A1 Martínez, Víctor G
A1 Morales, Lucía
A1 Pérez-Escavy, Mercedes
A1 Alonso-Sánchez, Miguel
A1 Lozano-Rodríguez, Roberto
A1 Cueto, Francisco J
A1 Aguirre, Luis A
A1 Guerrero-Ramos, Félix
A1 Paramio, Jesús M
A1 López-Collazo, Eduardo
A1 Dueñas, Marta
K1 HDACi
K1 bladder cancer
K1 tumor hybrid cells
K1 tumor microenvironment
AB Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1β. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b-EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.
SN 2072-6694
YR 2022
FD 2022-01-07
LK http://hdl.handle.net/10668/20866
UL http://hdl.handle.net/10668/20866
LA en
DS RISalud
RD Apr 7, 2025