Structure and function of β-arrestins, their emerging role in breast cancer, and potential opportunities for therapeutic manipulation

Shukla, Arun K.; Dwivedi-Agnihotri, Hemlata

doi:10.1016/bs.acr.2020.01.001

Cited by 20 publications

(16 citation statements)

References 87 publications

(108 reference statements)

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“…The role of β-Arrs in cancer invasion and metastasis is reported through various signaling pathways including mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK), Wnt/β-catenin, and phosphoinositide-3 kinase (PI3K)/Akt [9]. Other reports have proposed the direct implication of β-Arrs in diverse types of cancer phenotypes and their participation in different stages of oncogenesis including initiation, promotion and progression [10]. Breast cancer is the leading cause of cancer related mortality among females, where the triple negative breast cancer (TNBC) constitutes about 20% of cases worldwide [11].…”

Section: Introductionmentioning

confidence: 99%

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

et al. 2021

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Non-visual arrestins (β-arrestins) are endocytic proteins that mediate agonist activated GPCRs internalization and signaling pathways in an independent manner. The involvement of β-arrestins in cancer invasion and metastasis is increasingly reported. So, it is hypothesized that inhibition of β-arrstins may diminish the survival chances of cancer cells. This study aimed to evaluate the in vitro impact of inhibiting β-arrestins on the autophagic and/or apoptotic responsiveness of breast cancer cells.We used Barbadin to selectively inhibit β-Arr/AP2 interaction in AVP stimulated V2R receptor of triple negative breast cancer cells (MDA MB-231). Autophagy was assessed by the microtubule-associated protein 1 light chain 3-II (LC3II), apoptosis was measured by Annexin-V/PI staining and cell cycle distribution was investigated based upon the DNA content using ow cytometry. Barbadin reduced cell viability to 69.1% and increased the autophagy marker LC3 II and its autophagic effect disappeared in cells transiently starved in Earle's balanced salt solution (EBSS). Also, Barbadin mildly enhanced the expression of P62 mRNA and arrested 63.7% of cells in G0/G1 phase. In parallel, the drug induced apoptosis in 29.9% of cells (by AV/PI) and 27.8% of cells were trapped in sub-G1 phase. The apoptotic effect of Barbadin was enhanced when autophagy was inhibited by the PI3K inhibitor (Wortmannin).Conclusively, the data demonstrate the dual autophagic and apoptotic effects of β-βArr/AP2 inhibition in triple negative breast cancer cells. These observations nominate β-Arrs as selective targets in breast cancer treatment.Thus, this work was designed to explore the autophagic and apoptosis effects of the inhibition of β-Arr/AP2 interaction in hormonally stimulated breast cancer cells. Materials And MethodsKey Reagents: Barbadin (3-amino-5-(4-benzylphenyl)-3H,4H-thieno[2,3-d]pyrimidin-4-one) (Cat No. B118250), Arginine Vasopressin acetic acid salt (AVP) (Cat No. V991535) and Wortmannin (Cat No. W499400), were purchased from Toronto Research Chemicals, Toronto, Ontario, Canada). Trichostatin A (TSA) and dimethyl sulfoxide (DMSO) were from Sigma Chemicals, USA. Earle's balanced salt solution (EBSS) and other cell culture reagents (DMEM 4.5 g/L glucose with L glutamine, penicillin/streptomycin, fetal bovine serum (FBS) and Trypsin/EDTA) were from Lonza Pharma & Biotech. Cell culture and treatment MDA MB-231 cells [16] was generously provided by Department of Cancer Biology, NCI, Cairo University.Cells were cultured in Dulbecco's modi ed Eagle's Minimal Essential Medium (DMEM) supplemented with 10% heat inactivated FBS, 1% Penicillin/Streptomycin in a humidi ed atmosphere of 95% air and 5% CO 2 at 37 °C. Initially, cells were seeded with a low cell density then subcultured with particular densities in 100 mm, 6 wells, or 96 wells plates according to the experimental settings. Cell treatmentsAutophagy was induced by glucose oxygen deprivation, where cells were starved for 4 hours in EBSS, which does not contain nutrients nor growth factors, at...

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Section: Introductionmentioning

confidence: 99%

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

et al. 2021

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“…Also, the small sample size limited the number of confounders we could introduce in the matching process to not exceed the recommended variable to case ratio. In addition, we focused on a specific MOR expression; thus, the influence of polymorphisms, other cellular pathways such β-arrestins or cannabinoid receptors, and opioid antagonists administration cannot be evaluated ( 41 – 43 ). Second, our analysis is limited to a specific subset of patients, i.e., stage II and III colorectal cancer patients; thus, extrapolation to other populations should be done with caution.…”

Section: Discussionmentioning

confidence: 99%

Opioid Receptor Expression in Colorectal Cancer: A Nested Matched Case-Control Study

et al. 2022

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BackgroundThere is growing interest in the possible effect of perioperative anesthetic management on the growth and spread of cancer. The impact of perioperative use of opioids on cancer recurrence remains controversial and an assessment cannot yet be established based on current publications. This study aimed to assess the differential expression of opioid receptors between healthy and tumor tissues in patients with stage II and III colorectal cancer undergoing elective surgery by immunohistochemistry (IHC).MethodsPropensity–score matched case–control study nested in a retrospective cohort of patients with stage II or III colorectal. The primary endpoint was the difference in µ–opioid receptor (MOR) expression measured by IHC between tumor and healthy tissue in subject with or without recurrence. Secondary endpoints were to evaluate the differences in Opioid Growth Factor Receptor (OGFR), cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) in the matched sample and from a from samples of colorectal cancer stored in the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression Project (GTEx).ResultsThere was a significant difference in MOR receptor (median 3 [intequartile range IQR: 1–3] and 0 [IQR: 0–2], P<0.001) and OGFR receptor (median 6 [IQR: 5–6] and 2 [IQR: 1–2], P<0.001) in tumor and control tissue respectively. However, there were no significant differences in cAMP nor PKA expression between both types of tissues and in expression in any of the analyzed variables by recurrence status. The MOR and OGFR expression data from TCGA database were similar to our sample size data with lower expression of MOR and higher expression of OGFR in tumoural samples with a skewed distribution for MOR expression in tumor tissue both in patients with and without recurrence.ConclusionIn patients with stage II and III colorectal cancer, overall expression of MOR and OGFR was significantly increased but was not different between previously matched patients with or without recurrence. No differences were found in the analyzed metabolic pathway of cAMP–PKA: These results were confirmed by an in silico analysis of samples from the TCGA–GTEx database.

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“…Arrestin proteins perform a plethora of regulatory functions towards GPCRs that include the inhibition of G-protein binding and receptor trafficking, thanks to the direct binding with many components of the endocytic machinery [60]. Arrestins have also caught attention for their role in tumor progression and metastasis [61], with possible exploitation in cancer therapy [62].…”

Section: Molecular Players In Gpcr Desensitization: Grks Arrestins An...mentioning

confidence: 99%

Endomembrane-Based Signaling by GPCRs and G-Proteins

Liccardo

Luini

Martino

2022

Cells

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G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of specific transduction pathways. For many years, biologists thought that GPCR signaling occurred entirely on the plasma membrane. However, in recent decades, many lines of evidence have proved that the GPCRs and G-proteins may reside on endomembranes and can start or propagate signaling pathways through the organelles that form the secretory route. How these alternative intracellular signaling pathways of the GPCR and G-proteins influence the physiological and pathological function of the endomembranes is still under investigation. Here, we review the general role and classification of GPCRs and G-proteins with a focus on their signaling pathways in the membrane transport apparatus.

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Structure and function of β-arrestins, their emerging role in breast cancer, and potential opportunities for therapeutic manipulation

Cited by 20 publications

References 87 publications

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

β-Arrestin inhibition induces autophagy, apoptosis, G0/G1 cell cycle arrest in agonist-activated V2R receptor in breast cancer cells

Opioid Receptor Expression in Colorectal Cancer: A Nested Matched Case-Control Study

Endomembrane-Based Signaling by GPCRs and G-Proteins

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