The influence of a caveolin-1 mutant on the function of P-glycoprotein

Lee, Chih-Yuan; Lai, Ting-Yu; Tsai, Meng-Kun; Ou-Yang, Pu; Tsai, Chia Fen; Wu, S. C.; Hsu, Li-Chung; Chen, Jin‐Shing

doi:10.1038/srep20486

Cited by 15 publications

(10 citation statements)

References 36 publications

(47 reference statements)

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“…It has also been previously shown that overexpression of caveolin-1 sensitize doxorubicin resistant breast cancer cells by inhibiting P-glycoprotein transport activity [40]. The introduction of K176R mutation on Cav1 led to increased p-gp transport activity in Cav1 overexpressing non-small-cell lung cancer cells [41]. The inverse correlation between Cav1 and p-gp protein levels in ovarian cancer cells may result in enhanced chemo-sensitivity by the inhibition of p-gp protein levels or the activity by Cav1 overexpression.…”

Section: Discussionmentioning

confidence: 99%

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer

et al. 2018

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BackgroundCirculating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood.MethodsTo investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments.FindingsSubstantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages.InterpretationOur results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.

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Section: Discussionmentioning

confidence: 99%

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer

et al. 2018

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“…According to a recent publication, in addition to BBB, P‐gp is expressed in parenchymal central nervous system cells including neurons (Bernstein et al, ). There is also published information available indicating that, in the plasma membrane, P‐gp interacts physically and functionally with caveolin‐1 (Cav‐1), another membrane protein that is important for synaptic signalling, dendritic arborization, and neuronal survival (Lee et al, ). Cav‐1, in turn, regulates the expression of DISC‐1 (disrupted in schizophrenia‐1), long considered a schizophrenia candidate gene, and co‐localizes with DISC‐1 (as it does with P‐gp) in membrane caveolae (Kassan et al, ).…”

Section: Discussionmentioning

confidence: 99%

ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Papazisis

Goulas

Sarrigiannidis

et al. 2017

Human Psychopharmacology

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Objectives: The aim of our study was to examine the association between ABCB1 polymorphisms G2677T/A (rs2032582) and C3435T (rs1045642) and common CYP2D6 variants, with the response to antipsychotic treatment of psychotic patients, in a naturalistic setting, in Greece.Methods: One hundred patients suffering from schizophrenia and other psychotic disorders were included in the study. Dosages were normalized to chlorpromazine equivalents. Response following 1 month of treatment was assessed as either a continuous variable, using the distribution of the corrected Positive and Negative Syndrome Scale percent change, or as a dichotomous variable defined as the number of patients scoring ≥30% from the corrected baseline Positive and Negative Syndrome Scale score. Genotyping was achieved with established polymerase chain reaction-restriction fragment length polymorphism methods.Results: With response treated as a continuous variable, the homozygous recessive rs2032582 genotypes (TT) who were simultaneously carriers of a loss-of-function CYP2D6 allele (*4 or *5) responded significantly worse than the rest of the patients. Comparison of genotype frequencies revealed a statistically significant association of the above combination. No significant association between chlorpromazine equivalents and the tested genotypes was detected. Conclusion:We have detected a possible interaction between ABCB1 and CYP2D6 in affecting response of psychotic patients to drug treatment, in a naturalistic setting.

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“…In A549 and H460 cells, Cav-1 with lysine 176-to-arginine (K176R) mutant fails to form the Cav-1/P-gp complex, thus P-gp functions normally to accelerate the efflux of substrates (i.e., paclitaxel and doxorubicin). Moreover, they also found that Cav-1 K176R mutant could influence Cav-1 oligomerization, which is essential for caveolae structure and is probably the cause for inducing the disassociation of Cav-1 and P-gp [141].…”

Section: Cav-1 and Drug Resistancementioning

confidence: 97%

Multifaceted Roles of Caveolin-1 in Lung Cancer: A New Investigation Focused on Tumor Occurrence, Development and Therapy

Shi

Lai

et al. 2020

Cancers

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Lung cancer is one of the most common and malignant cancers with extremely high morbidity and mortality in both males and females. Although traditional lung cancer treatments are fast progressing, there are still limitations. Caveolin-1 (Cav-1), a main component of caveolae, participates in multiple cellular events such as immune responses, endocytosis, membrane trafficking, cellular signaling and cancer progression. It has been found tightly associated with lung cancer cell proliferation, migration, apoptosis resistance and drug resistance. In addition to this, multiple bioactive molecules have been confirmed to target Cav-1 to carry on their anti-tumor functions in lung cancers. Cav-1 can also be a predictor for lung cancer patients’ prognosis. In this review, we have summarized the valuable research on Cav-1 and lung cancer in recent years and discussed the multifaceted roles of Cav-1 on lung cancer occurrence, development and therapy, hoping to provide new insights into lung cancer treatment.

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The influence of a caveolin-1 mutant on the function of P-glycoprotein

Cited by 15 publications

References 36 publications

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer

ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting

Multifaceted Roles of Caveolin-1 in Lung Cancer: A New Investigation Focused on Tumor Occurrence, Development and Therapy

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