Levy Debora, de Melo Thatiana Correa, Oliveira Beatriz A, Paz Jessica L, de Freitas Fabio A, Reichert Cadiele O, Rodrigues Alessandro, Bydlowski Sergio P
Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil.
Departamento de Química, Universidade Federal de Sao Paulo, Diadema, SP, Brazil.
Biochem Biophys Rep. 2018 Dec 31;19:100604. doi: 10.1016/j.bbrep.2018.12.008. eCollection 2019 Sep.
Oxysterols are 27-carbon oxidation products of cholesterol metabolism. Oxysterols possess several biological actions, including the promotion of cell death. Here, we examined the ability of 7-ketocholesterol (7-KC), cholestane-3β-5α-6β-triol (triol), and a mixture of 5α-cholestane-3β,6β-diol and 5α-cholestane-3β,6α-diol (diol) to promote cell death in a human breast cancer cell line (MDA-MB-231). We determined cell viability, after 24-h incubation with oxysterols. These oxysterols promoted apoptosis. At least part of the observed effects promoted by 7-KC and triol arose from an increase in the expression of the sonic hedgehog pathway mediator, smoothened. However, this increased expression was apparently independent of sonic hedgehog expression, which did not change. Moreover, these oxysterols led to increased expression of LXRα, which is involved in cellular cholesterol efflux, and the ATP-binding cassette transporters, ABCA1 and ABCG1. Diols did not affect these pathways. These results suggested that the sonic hedgehog and LXRα pathways might be involved in the apoptotic process promoted by 7-KC and triol.
氧化甾醇是胆固醇代谢的27碳氧化产物。氧化甾醇具有多种生物学作用，包括促进细胞死亡。在此，我们检测了7-酮胆固醇（7-KC）、胆甾烷-3β-5α-6β-三醇（三醇）以及5α-胆甾烷-3β,6β-二醇和5α-胆甾烷-3β,6α-二醇混合物（二醇）在人乳腺癌细胞系（MDA-MB-231）中促进细胞死亡的能力。在用氧化甾醇孵育24小时后，我们测定了细胞活力。这些氧化甾醇促进了细胞凋亡。7-KC和三醇所观察到的至少部分效应源于音猬因子信号通路介质 smoothened表达的增加。然而，这种表达增加显然独立于音猬因子的表达，后者并未改变。此外，这些氧化甾醇导致参与细胞胆固醇外流的肝X受体α（LXRα）以及ATP结合盒转运蛋白ABCA1和ABCG1的表达增加。二醇不影响这些信号通路。这些结果表明，音猬因子和LXRα信号通路可能参与了7-KC和三醇所促进的凋亡过程。
