ADP-ribosylation factor 1 (ARF1) takes part in cell proliferation and cell adhesion-mediated drug resistance (CAM-DR)

Xu, Xiaohong; Wang, Qiru; He, Yunhua; Ding, Linlin; Zhong, Fei; Ou, Yangyu; Shen, Yun; Hong, Liu; He, Song

doi:10.1007/s00277-017-2949-2

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…Genes like Arnt1 , 37 Rab6a , 38 and Uhrf1 (39) regulate Mdr1 gene expression and sensitize cancer cells to anticancer drugs. Other differentially expressed genes on TRI-Gel treatment like Arf1 , 40 Rbpj , 41 Trim25 , 42 Usp24 , 43 DNAJB1 , 44 Mia3 , 45 Pex3 , 46 and Obfc1 (47) have been shown to be associated with drug resistance in different cancer models using diverse mechanisms. qRT-PCR confirmed significant downregulation of Arf1 (2.4-fold, p < 0.005), Arnt (3.3-fold, p < 0.05), Uhrf1 (sixfold, p < 0.0001), Trim25 (twofold, p < 0.001), Ndfip2 (1.9-fold, p < 0.05), and Rbpj (42-fold, p < 0.0001) on TRI-Gel treatment as compared to untreated tissues (Figure S14E).…”

Section: Resultsmentioning

confidence: 99%

A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

et al. 2019

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Rapid proliferation of cancer cells assisted by endothelial cell-mediated angiogenesis and acquired inflammation at the tumor microenvironment (TME) lowers the success rate of chemotherapeutic regimens. Therefore, targeting these processes using localized delivery of a minimally toxic drug combination may be a promising strategy. Here, we present engineering of a biocompatible self-assembled lithocholic acid-dipeptide derived hydrogel (TRI-Gel) that can maintain sustained delivery of antiproliferating doxorubicin, antiangiogenic combretastatin-A4 and anti-inflammatory dexamethasone. Application of TRI-Gel therapy to a murine tumor model promotes enhanced apoptosis with a concurrent reduction in angiogenesis and inflammation, leading to effective abrogation of tumor proliferation and increased median survival with reduced drug resistance. In-depth RNA-sequencing analysis showed that TRI-Gel therapy induced transcriptome-wide alternative splicing of many genes responsible for oncogenic transformation including sphingolipid genes. We demonstrate that TRI-Gel therapy targets the reversal of a unique intron retention event in β-glucocerebrosidase 1 (Gba1), thereby increasing the availability of functional Gba1 protein. An enhanced Gba1 activity elevates ceramide levels responsible for apoptosis and decreases glucosylceramides to overcome drug resistance. Therefore, TRI-Gel therapy provides a unique system that affects the TME via post-transcriptional modulations of sphingolipid metabolic genes, thereby opening a new and rational approach to cancer therapy.

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Section: Resultsmentioning

confidence: 99%

A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

et al. 2019

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“…In addition, our results suggest that different combinations of Golgi disruptors and antitumor drugs could be used to selectively target transforming pathways, with deleterious effects on the tumorigenic phenotype. In this regard, inhibition of ARF1 function has been tested as potential therapeutic target for cancer, including triple-negative breast cancer [ 32 , 70 , 72 , 83 , 96 , 114 , 115 ]. However, our results indicate a more complex relationship than anticipated between ARF1 function and the targets of ARF-GEFs inhibitors that could be exploited therapeutically.…”

Section: Resultsmentioning

confidence: 99%

Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling

et al. 2018

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Increasing evidence indicates that the Golgi apparatus plays active roles in cancer, but a comprehensive understanding of its functions in the oncogenic transformation has not yet emerged. At the same time, the Golgi is becoming well recognized as a hub that integrates its functions of protein and lipid biosynthesis to signal transduction for cell proliferation and migration in cancer cells. Nevertheless, the active function of the Golgi apparatus in cancer cells has not been fully evaluated as a target for combined treatment. Here, we analyzed the effect of perturbing the Golgi apparatus on the sensitivity of the MDA-MB-231 breast cancer cell line to the drugs Actinomycin D and Vinblastine. We disrupted the function of ARF1, a protein necessary for the homeostasis of the Golgi apparatus. We found that the expression of the ARF1-Q71L mutant increased the sensitivity of MDA-MB-231 cells to both Actinomycin D and Vinblastine, resulting in decreased cell proliferation and cell migration, as well as in increased apoptosis. Likewise, the combined treatment of cells with Actinomycin D or Vinblastine and Brefeldin A or Golgicide A, two disrupting agents of the ARF1 function, resulted in similar effects on cell proliferation, cell migration and apoptosis. Interestingly, each combined treatment had distinct effects on ERK1/2 and AKT signaling, as indicated by the decreased levels of either phospho-ERK1/2 or phospho-AKT. Our results suggest that disruption of Golgi function could be used as a strategy for the sensitization of cancer cells to chemotherapy.

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“…ARF1 has been associated with resistance to anticancer drugs in various cancers [ 281 , 282 , 283 , 284 , 285 ]. ARF1 is a member among 29 human ARF family members that belong to the small GTPase RAS superfamily [ 286 , 287 ].…”

Section: Resistance To Anti-egfr Therapeuticsmentioning

confidence: 99%

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

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et al. 2021

Pharmaceuticals

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Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis among patients with TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment in both clinical and preclinical settings. However, with the advantage of a number of clinically approved EGFR inhibitors (EGFRis), combination strategies have been explored as a promising approach to overcome the intrinsic resistance of TNBC to EGFRis. In this review, we analyzed the literature on the combination of EGFRis with other molecularly targeted therapeutics or conventional chemotherapeutics to understand the current knowledge and to provide potential therapeutic options for TNBC treatment.

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ADP-ribosylation factor 1 (ARF1) takes part in cell proliferation and cell adhesion-mediated drug resistance (CAM-DR)

Cited by 15 publications

References 31 publications

A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

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