Chemo‐small extracellular vesicles released in cisplatin‐resistance ovarian cancer cells are regulated by the lysosomal function

CERDA?TRONCOSO, CRISTÓBAL; GRÜNENWALD, FELIPE; ARIAS?MUÑOZ, ELOÍSA; CAVIERES, VIVIANA A.; CACERES?VERSCHAE, ALBANO; HERNÁNDEZ, SERGIO; GAETE?RAMÍREZ, BELÉN; ÁLVAREZ?ASTUDILLO, FRANCISCA; ACUÑA, RODRIGO A.; OSTROWSKI, MATIAS; BURGOS, PATRICIA V.; VARAS?GODOY, MANUEL

Journal of Extracellular Biology

Wiley

Año: 2024 vol. 3

2768-2811

Chemoresistance is a common problem in ovarian cancer (OvCa) treatment, whereresistant cells, in response to chemotherapy, secrete small extracellular vesicles(sEVs), known as chemo-sEVs, that transfer resistance to recipient cells. sEVs areformed as intraluminal vesicles (ILVs) within multivesicular endosomes (MVEs),whose trafficking is regulated by Ras-associated binding (RAB) GTPases that mediatesEVs secretion or lysosomal degradation. A decrease in lysosomal function can promote sEVs secretion, but the relationship between MVEs trafficking pathways andsEVs secretion in OvCa chemoresistance is unclear. Here, we show that A2780ciscisplatin (CCDP) resistant OvCa cells had an increased number of MVEs and ILVsstructures, higher levels of Endosomal Sorting Complex Required for Transport(ESCRTs) machinery components, and RAB27A compared to A2780 CDDP-sensitiveOvCa cells. CDDP promoted the secretion of chemo-sEVs in A2780cis cells, enrichedin DNA damage response proteins. A2780cis cells exhibited poor lysosomal function with reduced levels of RAB7, essential in MVEs-Lysosomal trafficking. Thesilencing of RAB27A in A2780cis cells prevents the Chemo-EVs secretion, reducesits chemoresistance and restores lysosomal function and levels of RAB7, switchingthem into an A2780-like cellular phenotype. Enhancing lysosomal function withrapamycin reduced chemo-sEVs secretion. Our results suggest that adjusting the balance between secretory MVEs and lysosomal MVEs trafficking could be a promisingstrategy for overcoming CDDP chemoresistance in OvCa.