System Xc− inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance

Wang, Fang; Oudaert, Inge; Tu, Chenggong; Maes, Anke; Vreken, Arne Van der; Vlummens, Philip; Bruyne, Elke De; Veirman, Kim De; Wang, Yanmeng; Fan, Rong; Massie, Ann; Vanderkerken, Karin; Shang, Peng; Menu, Eline

doi:10.1016/j.canlet.2022.215649

Cited by 18 publications

(18 citation statements)

References 35 publications

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“…Subsequently, intracellular glutamate is exported outside the cell by cystine/glutamate antiporter System Xc − . After binding to its receptor metabotropic glutamate receptor 3 (mGluR3, encoded by GRM3), extracellular glutamate activates mGluR3 to promote Rab27-dependent exosome release [12,183] (Fig. 6C).…”

Section: Glutamine and Glutamatementioning

confidence: 99%

“…Recently, it was reported that system Xc − mediated glutamate export enhanced exosome secretion in multiple myeloma and bone marrow stromal cells by upregulating the expression of Rab27a, TSG101, Alix, and VAMP7, thereby contributing to bortezomib resistance in multiple myeloma. Targeting system Xc − with the inhibitor sulfasalazine (SASP) or targeting GRM3 with the antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) reduced exosome secretion and countered bortezomib resistance in multiple myeloma [183]. However, although SASP treatment causes reactive oxygen species (ROS)-related apoptosis and suppresses cell growth in melanoma, it promotes the expression and exosomal release of PD-L1, leading to polarization of M2 macrophages and tolerance to anti-PD-1/PD-L1 therapy [233].…”

Section: Targeting the Glutamate/grm3/rab27a Pathwaymentioning

confidence: 99%

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Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

et al. 2022

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Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.

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Section: Glutamine and Glutamatementioning

confidence: 99%

Section: Targeting the Glutamate/grm3/rab27a Pathwaymentioning

confidence: 99%

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

et al. 2022

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“…Iron level is elevated in BMSC-interacting MM cells Studies have concluded that BMSCs induce multi-chemoresistance of MM cell [22][23][24] . We rstly veri ed that co-culture with BMSCs enhanced the chemoresistance to BTZ in MM cells (Fig s1A , s1B).…”

Section: Resultsmentioning

confidence: 99%

Roles of Iron in Chemoresistance of Multiple Myeloma Depends on the Interaction with Bone Marrow Stromal Cells

Jiang

Wang

et al. 2022

Preprint

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Bone marrow (BM) niche plays critical roles in promoting progression and chemoresistance of multiple myeloma (MM), but the iron metabolism bridging the malignant plasma cells and BM stromal cells (BMSCs) has not been well elucidated. Using in vitro and in vivo models of interaction of MM and BMSCs, we identified that iron level was augmented due to the elevated expression of transferrin in MM cells, and the accumulation of iron desensitized MM cells to proteasome inhibitors (PIs) treatment and promoted productions of cholesterol and lanosterol. Simultaneously, direct contact with BMSCs remarkably upregulated the protein level of GPX4, a ROS eraser, to obviate ferroptosis in MM cells. Mechanistic studies revealed that CD40/CD40 ligand (CD40L) signaling promoted the expressions of transferrin and SUMO-specific protease 3 (SENP3), and SENP3 stabilized GPX4 protein via deSUMOylation modification. GPX4 inhibitor induced ferroptosis was cell-cell contact dependent, since blocking CD40/CD40L interaction, or depletion of Cd40l in BMSCs from Cd40lfl/fl;Prx1Cre/+ mice, eliminated the anti-MM efficacy of RSL3 in the Vk*MYC mouse model of myeloma, but not in the patient-derived xenografts (PDX) model. Our study deciphers mechanism of iron metabolism in regulating MM chemoresistance, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

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“…The use of a system Xc − inhibitor, sulfasalazine, could reduce MM resistance to bortezomib induced by BMSCs, thus enhancing anti-MM effects. [241] Targeting EV cargos that are involved in cancer drug resistance may be more practical than systematically blocking the release of EVs. Treatment with docosahexaenoic acid (DHA), a natural compound with anticancer activity, could alter the miRNA profile of exosomes from breast cancer cells.…”

Section: Targeting Ev-mediated Crosstalk In Cancer Drug Resistancementioning

confidence: 99%

“…The use of a system Xc − inhibitor, sulfasalazine, could reduce MM resistance to bortezomib induced by BMSCs, thus enhancing anti‐MM effects. [ 241 ]…”

Section: The Potential Of Evs In Overcoming Cancer Drug Resistancementioning

confidence: 99%

Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications

Yang

et al. 2022

Advanced Science

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Extracellular vesicles (EVs) are cell-derived nanosized vesicles that mediate cell-to-cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial-mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed.

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System Xc− inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance

Cited by 18 publications

References 35 publications

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Roles of Iron in Chemoresistance of Multiple Myeloma Depends on the Interaction with Bone Marrow Stromal Cells

Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications

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