The impact of colon cancer derived exosomes on survival and chemoresistance signaling pathway

Abstract

Resistance to chemotherapy is a serious obstacle in the treatment of colon cancer. Previous studies have shown that exosomes play an essential role in creating drug resistance in tumor cells through the transfer of active proteins and genetic materials to nearby cells. Here, the role of colon cancer-derived exosomes on the survival and drug resistance of recipient cells is investigated. Methods: The effect of exosomes derived from colon cancer on survival and resistance to oxaliplatin in recipient cells and potential underlying mechanisms were investigated using MTT, flow cytometry, colony formation, scratch test, qRT-PCR and western blot methods. For this purpose, exosomes were isolated from cell culture medium using ultracentrifuge and confirmed by different assays. Results: The isolated exosomes had a spherical shape and a diameter of about 100 nm. Western blot results showed that exosomes isolated from resistant cells (Exo/R) have increased leveles of Nrf2 compared to exosomes derived from sensitive cells (Exo/S) (p < 0.05). In addition, incubation of sensitive cells (LS174T/S) with Exo/R increased the IC50 values and decreased the apoptosis rate in response to oxaliplatin treatment (P<0.05). Incubation of LS174T/S cells with Exo/R significantly increased the expression of Nrf2 and P-glycoprotein (P-gp) compared to untreated LS174T/S cells (P<0.05). In line with these changes, lower intracellular rhodamine 123 content was found in Exo/R-treated cells compared to untreated LS174T/S cells. Also, the migration and clonogenic capacity of LS174T/S cells increased significantly after incubation with Exo/R. It is noteworthy that inhibiting Nrf2 with brusatol as its specific inhibitor diminished these effects.