βArrestin2 Mediates Renal Cell Carcinoma Tumor Growth

Masannat, Jude; Purayil, Hamsa Thayele; Zhang, Yushan; Russin, Michelle; Mahmud, Iqbal; Kim, Wanju; Daaka, Yehia

doi:10.1038/s41598-018-23212-w

Cited by 19 publications

(18 citation statements)

References 44 publications

(49 reference statements)

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“…In prostate cancer, β-arr2 inhibits cell viability and proliferation by downregulation of FOXO1 and represses AR signaling, and AR expression/activity negatively correlates with β-arr2 expression (Lakshmikanthan et al., 2009; Duan et al., 2015). By contrast, other results are consistent with the idea that β-arr2 action provides a supportive role in the development of human tumors, and β-arr2 is overexpressed in different human tumors, including breast and renal cell carcinoma, correlating with advanced stage and decreased patient survival, and mediates different tumor-promoting effects, such as cell migration and invasion (Sun et al., 2002; Ge et al., 2004; Alemayehu et al., 2013; Masannat et al., 2018). In both myeloid leukemia and ovarian cancer cells, the cross-signaling between β-arr2 and Wnt controls cell proliferation and metastasis through the interaction with c-Src followed by EGFR transactivation (Luttrell et al., 1999; Rosanò et al., 2009).…”

Section: Role Of β-Arr2 In Cancer Progressionsupporting

confidence: 81%

New Routes in GPCR/β-Arrestin-Driven Signaling in Cancer Progression and Metastasis

Bagnato

Rosanò

2019

Front. Pharmacol.

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Tumor cells acquire invasive and metastatic behavior by sensing changes in the localization and activation of signaling pathways, which in turn determine changes in actin cytoskeleton. The core-scaffold machinery associated to β-arrestin (β-arr) is a key mechanism of G-protein coupled receptors (GPCR) to achieve spatiotemporal specificity of different signaling complexes driving cancer progression. Within different cellular contexts, the scaffold proteins β-arr1 or β-arr2 may now be considered organizers of protein interaction networks involved in tumor development and metastatic dissemination. Studies have uncovered the importance of the β-arr engagement with a growing number of receptors, signaling molecules, cytoskeleton regulators, epigenetic modifiers, and transcription factors in GPCR-driven tumor promoting pathways. In many of these molecular complexes, β-arrs might provide a physical link to active dynamic cytoskeleton, permitting cancer cells to adapt and modify the tumor microenvironment to promote the metastatic spread. Given the complexity and the multidirectional β-arr-driven signaling in cancer cells, therapeutic targeting of specific GPCR/β-arr molecular mechanisms is an important avenue to explore when considering future new therapeutic options. The focus of this review is to integrate the most recent developments and exciting findings of how highly connected components of β-arr-guided molecular connections to other pathways allow precise control over multiple signaling pathways in tumor progression, revealing ways of therapeutically targeting the convergent signals in patients.

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Section: Role Of β-Arr2 In Cancer Progressionsupporting

confidence: 81%

New Routes in GPCR/β-Arrestin-Driven Signaling in Cancer Progression and Metastasis

Bagnato

Rosanò

2019

Front. Pharmacol.

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“…Among the increased proteins following RBPMS knockdown, the two ARRB members—ARRB1 and ARRB2—are deregulated in many cancer types and have been linked to the inhibition of the senescence and growth as well as the promotion of the self-renewal, progression, and invasion of cancerous cells [ 39 , 40 , 81 ]. Moreover, CPT1A plays a crucial role in radioresistant and chemoresistant phenotypes in diverse cancer types [ 41 , 42 , 82 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

Rabelo-Fernández

Santiago-Sánchez

Sharma

et al. 2022

IJMS

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Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan–Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells.

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“…Subrenal capsule implantation was performed as we described. 20,28,29 Briefly, 5-6-week old male nude mice (Envigo) were grouped according to body weight. Soft collagen pellets containing 1 × 10 6 cells were placed under the capsule of the left kidney.…”

Section: Tumor Growth In Vivomentioning

confidence: 99%

βArrestin1 regulates glucocorticoid receptor mitogenic signaling in castration‐resistant prostate cancer

Purayil

Daaka

2022

The Prostate

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Background: Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in males. The disease is initially treated with methods that inhibit androgen receptor (AR) signal transduction.Laboratory-based and clinical studies have identified alternative pathways that cause the failure of AR signal inhibition and consequent development of castrationresistant prostate cancer (CRPC). Glucocorticoid receptor (GR) signaling is activated in certain PC patients and promotes the emergence of CRPC, although by as yet incompletely understood mechanisms. We have previously demonstrated that ubiquitous βarrestin1 (βArr1) expression levels are linked to PC progression. Here, we consider the possibility that βArr1 interacts with and activates GR in model CRPC cells.Methods: Bioinformatic analysis of tumor xenograft and human PC datasets was used to correlate the expression of βArr1 and GR. Western blot, immunohistochemistry and immunofluorescence microscopy, and subcellular fractionation were used to determine protein expression level and localization. Immunoprecipitation was applied to detect protein-protein interactions. RNA expression levels were determined using quantitative reverse transcription-polymerase chain reaction. Prostate sphere analysis was used to assess the rate of growth and invasion. The xenograft tumor implantation method was used to determine the tumor growth rate, local invasion, and metastasis.Results: Elevated expression of βArr1 positively correlated with increased GR expression and function in CRPC xenograft and in human PC patients. βArr1 is expressed in the cell cytosol and nucleus, and it formed a complex with GR in the nucleus and not cytosol. Depletion of βArr1 in AR-null CRPC cells inhibited GR function and CRPC growth and invasion in both in vitro and in vivo settings.Conclusions: βArr1 binds GR that initiates mitogenic signaling cascades involved in the progression of PC to CRPC. The targeting of the βArr1-GR axis may provide a new opportunity to better manage the CRPC disease.

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βArrestin2 Mediates Renal Cell Carcinoma Tumor Growth

Cited by 19 publications

References 44 publications

New Routes in GPCR/β-Arrestin-Driven Signaling in Cancer Progression and Metastasis

New Routes in GPCR/β-Arrestin-Driven Signaling in Cancer Progression and Metastasis

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

βArrestin1 regulates glucocorticoid receptor mitogenic signaling in castration‐resistant prostate cancer

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