Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells

Tu, Chenggong; Du, Zhimin; Zhang, Hui; Feng, Yueyuan; Qi, Yujun; Zheng, Yu; Liu, Jinbao; Wang, Jinheng

doi:10.7150/thno.47996

Cited by 35 publications

(18 citation statements)

References 26 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bone marrow–derived mesenchymal stem cells (BMSCs) are non-hematopoietic stem cells with multi-differentiation potentials, and BMSCs are the most commonly used stem cells in aspects of cell therapy and tissue repair ( 4 , 5 ). Notably, extracellular vesicles (EVs) derived from BMSCs have been implicated in the progression of several cancers such as lung cancer ( 6 ), cervical cancer ( 7 ), and myeloma ( 8 ). As a promising cell-free therapy, EVs function through shuttling bioactive cargoes such as proteins, RNAs, mRNAs, microRNAs (miRNAs), lipids, and organelles to recipient cells and have higher safety profile ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell–Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis

2021

View full text Add to dashboard Cite

Emerging evidence indicates that extracellular vesicle (EV)-encapsulated circRNAs have the potential diagnostic and prognostic values for malignancies. However, the role of circNRIP1 in osteosarcoma remains unclear. We herein investigated the therapeutic potential of circNRIP1 delivered by bone marrow mesenchymal stem cell–derived EVs (BMSC-EVs) in osteosarcoma. The expression of circNRIP1 was examined in the clinical tissue samples of osteosarcoma patients, after which the downstream genes of circNRIP1 were bioinformatically predicted. Gain- and loss-of function assays were then performed in osteosarcoma cells with manipulation of circNRIP1 and miR-532-3p expression. EVs isolated from BMSCs were characterized and co-cultured with osteosarcoma cells to examine their effects on cell phenotypes, as reflected by CCK-8 and Transwell assays. Further, a mouse model of tumor xenografts was established for in vivo substantiation. circNRIP1 was upregulated in osteosarcoma tissues and cells. Overexpression of circNRIP1 promoted the proliferative, migratory, and invasive potential of osteosarcoma cells. Co-culture data showed that BMSC-EVs could transfer circNRIP1 into osteosarcoma cells where it competitively bound to miR-532-3p and weakened miR-532-3p’s binding ability to AKT3. By this mechanism, the PI3K/AKT signaling pathway was activated and the malignant characteristics of osteosarcoma cells were stimulated. In vivo experimental results unveiled that circNRIP1-overexpressing BMSC-EVs in nude mice resulted in enhanced tumor growth. In conclusion, the BMSC-EV-enclosed circNRIP1 revealed a new molecular mechanism in the pathogenesis of osteosarcoma, which might provide a novel therapeutic target for osteosarcoma.

show abstract

Section: Introductionmentioning

confidence: 99%

CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell–Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis

2021

View full text Add to dashboard Cite

show abstract

“…In addition, other authors also indicated that the endocytic pathway seems to be impaired in drug-resistant cells [ 58 , 59 ]. More recently, the impact of the endocytic pathway regulation in drug resistance mediated by EVs has been also assessed: Rab7A was shown to regulate cisplatin resistance by determining alterations in late endocytic trafficking and subsequent drug efflux through EVs [ 60 ]; chemotherapeutic agents were shown to stimulate the secretion and recycling of P-gp-enriched EVs through the dysregulation of endocytic pathway [ 61 ] and it was found that manipulation of the endocytic pathway attenuates extracellular vesicle-induced reduction in chemosensitivity to bortezomib in multiple myeloma cells [ 62 ]. Altogether, this evidence demonstrates the importance of unravelling the role of endocytic pathway regulation in drug resistance mediated by EVs.…”

Section: Discussionmentioning

confidence: 99%

Different Ability of Multidrug-Resistant and -Sensitive Counterpart Cells to Release and Capture Extracellular Vesicles

Sousa

Lima

Lopes-Rodrigues

et al. 2021

Cells

View full text Add to dashboard Cite

Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MDR is a phenomenon by which tumor cells become resistant to several unrelated drugs. Some studies have previously described the important role of extracellular vesicles (EVs) in the dissemination of a MDR phenotype. EVs’ cargo may include different players of MDR, such as microRNAS and drug-efflux pumps, which may be transferred from donor MDR cells to recipient drug-sensitive counterparts. The present work aimed to: (i) compare the ability of drug-sensitive and their MDR counterpart cells to release and capture EVs and (ii) study and relate those differences with possible distinct fate of the endocytic pathway in these counterpart cells. Our results showed that MDR cells released more EVs than their drug-sensitive counterparts and also that the drug-sensitive cells captured more EVs than their MDR counterparts. This difference in the release and capture of EVs may be associated with differences in the endocytic pathway between drug-sensitive and MDR cells. Importantly, manipulation of the recycling pathway influenced the response of drug-sensitive cells to doxorubicin treatment.

show abstract

“…Inhibition of MM-EVs endocytosis by BMSCs by various endocytosis inhibitors (i.e., heparin, dynasore and omeprazole), prevents activation of intracellular pathways, i.e., STAT1, STAT3, and ERK1/2, which are associated with cell survival and proliferation [117]. Moreover, Tu et al [118] have shown that EVs confer resistance to bortezomib. Blockade of endocytosis by chemical inhibitors reduces the internalization of BMSCs-EVs and sensitizes MM cells to bortezomib treatment in vitro and in vivo [118].…”

Section: Therapeutic Perspectivementioning

confidence: 99%

“…Moreover, Tu et al [118] have shown that EVs confer resistance to bortezomib. Blockade of endocytosis by chemical inhibitors reduces the internalization of BMSCs-EVs and sensitizes MM cells to bortezomib treatment in vitro and in vivo [118]. Other studies have explored the possibility of enhancing the EVs immune activity [119,120].…”

Section: Therapeutic Perspectivementioning

confidence: 99%

Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression

Saltarella

Lamanuzzi

Apollonio

et al. 2021

Cells

View full text Add to dashboard Cite

Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring.

show abstract

Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells

Cited by 35 publications

References 26 publications

CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell–Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis

CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell–Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis

Different Ability of Multidrug-Resistant and -Sensitive Counterpart Cells to Release and Capture Extracellular Vesicles

Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression

Contact Info

Product

Resources

About