Beevi Syed Sultan, Bhale Aishwarya Sudam, Verma Vinod Kumar, Darapuneni Radhika Chowdary
Cancer Biology Division, KIMS Foundation and Research Center, Krishna Institute of Medical Sciences (KIMS) Hospitals, Secunderabad, Telangana, India.
Diagnostics Division, Krishna Institute of Medical Sciences, (KIMS) Hospitals, Secunderabad, Telangana, India.
Cell Biochem Biophys. 2025 Apr 11. doi: 10.1007/s12013-025-01744-z.
Tumor-derived exosomes (TDEs) play a crucial role in horizontally transferring oncogenic information from tumors to other sites. Cellular cholesterol homeostasis has emerged as a significant factor influencing exosomal biogenesis and cellular release. In this study, we employed U18666A to induce cholesterol accumulation within the late endosomes of MDA-MB231 cells. We assessed the capacity of exosomes derived from U18666A-treated and untreated cells to initiate malignant transformation in HEK293 cells. Exosomes were isolated and characterized from both untreated and U18666A-treated MDA-MB231 cells, and HEK293 cells. The impact of exosomes derived from untreated MDA-MB231 cells (referred to as UCE) and U18666A-treated MDA-MB231 cells (referred to as UTCE) to induce transformation on HEK293 cells was investigated. Exosomes derived from MDA-MB231 cells induced proliferation, migration, malignant transformation, and epithelial-mesenchymal transition (EMT) process in HEK293 cells. Treatment with U18666A resulted in cholesterol accumulation within late endosomes, consequently markedly reversing the EMT process in MDA-MB231 cells. This treatment diminished the content of Tumor-derived exosomes released by the cancer cells, rendering them less oncogenic. This reduction in oncogenic potential was evident as they lost the ability to induce malignant transformation in recipient HEK293 cells. Modulating cholesterol homeostasis and disrupting the supply of cholesterol to aggressive cancer cells emerges as an appealing strategy to restrain the release of Tumor-derived exosomes and subsequently mitigate their contributory role in driving cancer progression and metastasis.
肿瘤衍生外泌体（TDEs）在将致癌信息从肿瘤水平转移至其他部位的过程中发挥着关键作用。细胞胆固醇稳态已成为影响外泌体生物发生和细胞释放的重要因素。在本研究中，我们使用U18666A诱导MDA - MB231细胞晚期内体中的胆固醇积累。我们评估了来自经U18666A处理和未处理细胞的外泌体在HEK293细胞中引发恶性转化的能力。从未处理和经U18666A处理的MDA - MB231细胞以及HEK293细胞中分离并鉴定了外泌体。研究了来自未处理的MDA - MB231细胞（称为UCE）和经U18666A处理的MDA - MB231细胞（称为UTCE）的外泌体对HEK293细胞诱导转化的影响。来自MDA - MB231细胞的外泌体在HEK293细胞中诱导增殖、迁移、恶性转化和上皮 - 间质转化（EMT）过程。用U18666A处理导致晚期内体中胆固醇积累，从而显著逆转MDA - MB231细胞中的EMT过程。这种处理减少了癌细胞释放的肿瘤衍生外泌体的含量，使其致癌性降低。这种致癌潜力的降低很明显，因为它们失去了在受体HEK293细胞中诱导恶性转化的能力。调节胆固醇稳态并中断向侵袭性癌细胞的胆固醇供应成为一种有吸引力的策略，以抑制肿瘤衍生外泌体的释放，并随后减轻它们在驱动癌症进展和转移中的作用。
