β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer

Abstract

b-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that b-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. b-Arrestin-1 (ARRB1) and b-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n ¼ 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, diseasespecific-mortality, and failure to Gemcitabine þ Cisplatin (GþC) chemotherapy; $80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.

Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches

“…Arrestin beta 1 (ARRB1) is one of the beta arrestins regulating various cellular physiologic processes, and have been demonstrated to have pro-tumorigenic effects [35,36]. Kallifatidis et al recently reported increased ARRB1 expression in bladder cancer cells, and ARRB1 gene knockout reversed the aggressive phenotype of bladder cancer cell lines [37]. MiR-185-3p is a potential oncosuppressor miRNA evident in nasopharyngeal carcinoma (NPC), and the inhibition of miR-185-3p promoted invasion and metastasis of NPC cells [38].…”

ARRB1 Regulates Metabolic Reprogramming to Promote Glycolysis in Stem Cell-Like Bladder Cancer Cells

“…ARRB1 knock out cells were generated by CRISPR/Cas9 genome editing technology and evaluated as described in our previous work [ 19 ].…”

“…However, in certain circumstances, β-arrestins can function as adaptor molecules that mediate G-protein independent signaling by serving as scaffolds that link signaling networks [ 18 ]. Our previous work shows that β-arrestins regulate stem cell properties in BC [ 19 ]. We have demonstrated that ARRB1 regulates the CSC markers CD44 and Bmi1 [ 19 ].…”

“…Our previous work shows that β-arrestins regulate stem cell properties in BC [ 19 ]. We have demonstrated that ARRB1 regulates the CSC markers CD44 and Bmi1 [ 19 ]. The latter is a transcription factor involved in self-renewal and regulation of ROS [ 20 ].…”

Can new immunoassay techniques improve bladder cancer diagnostics With protein biomarkers?

“…Proteins specific to immune privileged zones, such as cancer-retina antigens, were shown to be aberrantly expressed in malignant tumors ( Golovastova et al, 2014 ). Among these proteins, recoverin ( Golovastova et al, 2016 ) and arrestin ( Baldin et al, 2019 ; Kallifatidis et al, 2019 ) were found to be highly predictive biomarkers of renal cell carcinoma and BC. However, they have never been considered as low-invasive blood or urine biomarkers.…”