Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles - 28/03/23
Abstract |
Ocular retinoblastoma malignancies, which develop into metastatic phenotypes, result in poor prognosis and survival for infant and child patients. To improve the prognosis of metastatic retinoblastoma, it is important to identify novel compounds with less toxic side effects and higher therapeutic efficacy compared to existing chemotherapeutics. Piperlongumine (PL), a neuroprotective, plant-derived compound has been explored for its anticancer activities both in vitro and in vivo. Here, we analyze the potential efficacy of PL for metastatic retinoblastoma cell treatment. Our data reveal that PL treatment significantly inhibits cell proliferation in metastatic retinoblastoma Y79 cells compared to the commonly used retinoblastoma chemotherapeutic drugs carboplatin, etoposide, and vincristine. PL treatment also significantly increases cell death compared to treatment with other chemotherapeutic drugs. PL-induced cell-death signaling was associated with significantly higher caspase 3/7 activities and greater loss of mitochondrial membrane potential. PL was also internalized into Y79 cells with an estimated concentration of 0.310pM and expression analysis revealed reduced MYCN oncogene levels. We next examined extracellular vesicles derived from PL-treated Y79 cells. Extracellular vesicles in other cancers are pro-oncogenic, mediating systemic toxicities via the encapsulation of chemotherapeutic drugs. Within metastatic Y79 EV samples, an estimated PL concentration of 0.026pM was detected. PL treatment significantly downregulated Y79 EV cargo of the oncogene MYCN transcript. Interestingly, non-PL-treated Y79 cells incubated with EVs from PL-treated cells exhibited significantly reduced cell growth. These findings indicate that in metastatic Y79 cells, PL exhibits potent anti-proliferation effects and oncogene downregulation. Importantly, PL is also incorporated into extracellular vesicles released from treated metastatic cells with measurable anti-cancer effects on target cells at a distance from the site of primary treatment. The use of PL in the treatment of metastatic retinoblastoma may reduce primary tumor proliferation and inhibit metastatic cancer activity systemically via extracellular vesicle circulation.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Piperlongumine direct and extracellular vesicle-mediated anti-cancer activity in chemoresistant retinoblastoma cells. 1) Piperlongumin enters retinoblastoma cell, 2) MYCN RNA is downregulated 3) cell proliferation is reduced, 4) mitochondria membrane depolarized, and 5) caspase3/7 increased. Next, 6) extracellular vesicles with piperlongumin cargo are released from treated cells, 7) taken up by untreated cells leading to 8) downregulation of MYCN RNA and 9) significantly reduced proliferation.
Piperlongumine direct and extracellular vesicle-mediated anti-cancer activity in chemoresistant retinoblastoma cells. 1) Piperlongumin enters retinoblastoma cell, 2) MYCN RNA is downregulated 3) cell proliferation is reduced, 4) mitochondria membrane depolarized, and 5) caspase3/7 increased. Next, 6) extracellular vesicles with piperlongumin cargo are released from treated cells, 7) taken up by untreated cells leading to 8) downregulation of MYCN RNA and 9) significantly reduced proliferation.ga1Le texte complet de cet article est disponible en PDF.
Highlights |
• | Piperlongumine (PL) decreases chemoresistant metastatic retinoblastoma (RB) MYCN expression and cell proliferation. |
• | PL increases cell death, caspase 3/7 activities, and loss of mitochondrial membrane potential in chemoresistant RB cells. |
• | RB cells internalize and carry PL in extracellular vesicles that decrease MYCN and cell proliferation in recipient cells. |
• | The use of PL in RB treatment may inhibit metastatic cancer activity systemically via extracellular vesicle circulation. |
Keywords : Metastatic retinoblastoma, Piperlongumine, Extracellular vesicles, Chemotherapeutic drugs, Chemoresistance, MYCN
Plan
Vol 161
Article 114554- mai 2023 Retour au numéro
Article précédent
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