Colín-Val Zaira, López-Díazguerrero Norma Edith, López-Marure Rebeca
Departamento de Fisiología, Instituto Nacional de Cardiología "Ignacio Chávez", Ciudad de México, Mexico; Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Mexico.
Laboratorio de Bioenergética y Envejecimiento Celular, Departamento de Ciencias de la Salud, UAM-I, Mexico.
J Steroid Biochem Mol Biol. 2021 Apr;208:105818. doi: 10.1016/j.jsbmb.2021.105818. Epub 2021 Jan 27.
Cancer is one of the leading causes of death worldwide, and breast cancer is the most common among women. Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in human serum, inhibits proliferation and migration of breast cancer cells, modulating the expression of proteins involved in mesenchymal-epithelial transition (MET). However, the underlying molecular mechanisms are not fully understood. DHEA effects on the triple-negative breast cancer cell line MDA-MB-231 (mesenchymal stem-like) could be exerted by binding to receptors tyrosine kinase (RTKs) and signaling through MEK/ERK and/or PI3K/Akt pathways. In this study, MDA-MB-231 cells were exposed to DHEA in the presence of pharmacological inhibitors of these pathways and a siRNA against PIK3CA gene, which blocks PI3K pathway. Cell proliferation was measured by crystal violet staining, migration by the wound healing and transwell assays, and MET protein expression by western blot. A xenograft tumor growth in nude mice (nu/nu) using a siRNA against PI3K was also performed. Results showed that neither of the inhibitors used reverted the antiproliferative activity of DHEA. However, wortmannin and LY294002, inhibitors of the PI3K/Akt pathway, abolished the up- and down-regulation of E- and N-cadherin expression respectively, and inhibition of migration induced by DHEA in MDA-MB-231 cells. The siRNA that blocks the PI3K pathway, abolished the effects of DHEA on proliferation, migration, MET proteins expression and the growth of tumors in nude mice. In conclusion, these results suggest that PI3K/Akt pathway participates in the effects of DHEA on breast cancer cells.
癌症是全球主要死因之一，而乳腺癌是女性中最常见的癌症。脱氢表雄酮（DHEA）是人体血清中含量最丰富的类固醇激素，可抑制乳腺癌细胞的增殖和迁移，调节参与间充质-上皮转化（MET）的蛋白质表达。然而，其潜在的分子机制尚未完全明确。DHEA对三阴性乳腺癌细胞系MDA-MB-231（间充质干细胞样）的作用可能是通过与受体酪氨酸激酶（RTKs）结合，并通过MEK/ERK和/或PI3K/Akt信号通路发挥作用。在本研究中，MDA-MB-231细胞在这些信号通路的药理学抑制剂以及针对PIK3CA基因的小干扰RNA（siRNA，可阻断PI3K信号通路）存在的情况下暴露于DHEA。通过结晶紫染色测定细胞增殖，通过伤口愈合实验和Transwell实验测定细胞迁移，通过蛋白质免疫印迹法测定MET蛋白表达。还利用针对PI3K的siRNA在裸鼠（nu/nu）中进行了异种移植瘤生长实验。结果显示，所使用的任何一种抑制剂均未逆转DHEA的抗增殖活性。然而，PI3K/Akt信号通路的抑制剂渥曼青霉素和LY294002分别消除了DHEA诱导的E-钙黏蛋白表达上调和N-钙黏蛋白表达下调，并消除了DHEA对MDA-MB-231细胞迁移的抑制作用。阻断PI3K信号通路的siRNA消除了DHEA对细胞增殖、迁移、MET蛋白表达以及裸鼠肿瘤生长的影响。总之，这些结果表明PI3K/Akt信号通路参与了DHEA对乳腺癌细胞的作用。
