Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.
Carolina RubioJosé Avendaño-OrtizRaquel Ruiz-PalomaresViktoriya KaraivanovaOmaira AlberquillaRebeca Sánchez-DomínguezJosé Carlos Casalvilla-DueñasKarla Montalbán-HernándezIris LodewijkMarta Rodríguez-IzquierdoEster Munera-MaravillaSandra P NunesCristian Suárez-CabreraMiriam Pérez-CrespoVictor M G MartinezLucía MoralesMercedes Pérez-EscavyMiguel Alonso-SánchezRoberto Lozano-RodríguezFrancisco J CuetoLuis Augusto AguirreFélix Guerrero-RamosJesus M ParamioEduardo López-CollazoMarta DueñasPublished in: Cancers (2022)
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.
Keyphrases
- cell cycle arrest
- cell death
- poor prognosis
- pi k akt
- cell proliferation
- stem cells
- long non coding rna
- endothelial cells
- signaling pathway
- epithelial mesenchymal transition
- high glucose
- end stage renal disease
- dna methylation
- chronic kidney disease
- adipose tissue
- ejection fraction
- drug induced
- newly diagnosed
- cell therapy
- cancer stem cells
- circulating tumor cells
- transcription factor
- gene expression
- mesenchymal stem cells
- induced pluripotent stem cells
- immune response
- peritoneal dialysis
- prognostic factors
- acute myeloid leukemia
- squamous cell
- electronic health record
- nk cells
- squamous cell carcinoma
- deep learning
- replacement therapy
- patient reported
- smoking cessation