Potočnjak Iva, Šimić Lidija, Vukelić Iva, Batičić Lara, Domitrović Robert
Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Croatia.
Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Croatia.
Chem Biol Interact. 2022 Aug 25;363:110010. doi: 10.1016/j.cbi.2022.110010. Epub 2022 Jun 9.
Oleanolic acid (OA) is a natural compound that possesses numerous beneficial health effects, including anticancer activity. The current study aimed to investigate the role of forkhead box O3a (FOXO3a) in autophagy/mitophagy by OA in HCT116 cell line. OA dose-dependently reduced viability of HCT116 cells, with IC = 29.8 μΜ. The expression of cleaved caspase-3 and poly (ADP-ribose) polymerase 1 increased after OA treatment, suggesting induction of apoptosis. Concurrently, OA induced autophagy, evidenced by increased expression of Beclin-1, autophagy-related protein 5 and microtubule-associated protein1A/1B-light chain 3 beta (LC3B), which played a prosurvival role. The induction of mitophagy was suggested by increased expression of p62 and PTEN-induced kinase 1 and reduced expression of translocase of outer mitochondrial membrane 20, which colocalized with LC3B. OA also induced nuclear accumulation of forkhead box O3a (FOXO3a). The cytotoxic activity of OA coincided with upregulation of p38. Inhibition of p38 led to increase in FOXO3a and NAD-dependent deacetylase sirtuin 6 expression. In vivo, OA inhibited tumor growth in colon cancer xenograft mice. Our results suggest concomitant induction of apoptosis and prosurvival mitophagy by OA in colon cancer via p38/FOXO3a/Sirt6 signaling. Additionally, our data demonstrate that OA can chemosensitize colon cancer cells to 5-fluorouracil (5-FU).
齐墩果酸（OA）是一种天然化合物，具有多种有益的健康功效，包括抗癌活性。本研究旨在探讨叉头框O3a（FOXO3a）在OA诱导HCT116细胞系自噬/线粒体自噬中的作用。OA剂量依赖性地降低了HCT116细胞的活力，IC = 29.8 μΜ。OA处理后，裂解的半胱天冬酶-3和聚（ADP-核糖）聚合酶1的表达增加，提示诱导了细胞凋亡。同时，OA诱导了自噬，这通过Beclin-1、自噬相关蛋白5和微管相关蛋白1A/1B轻链3β（LC3B）表达的增加得以证明，这些蛋白发挥了促生存作用。p62和PTEN诱导激酶1表达增加以及外膜线粒体转位酶20表达降低，且与LC3B共定位，提示了线粒体自噬的诱导。OA还诱导了叉头框O3a（FOXO3a）的核积累。OA的细胞毒性活性与p38的上调一致。抑制p38导致FOXO3a和NAD依赖性脱乙酰酶沉默调节蛋白6表达增加。在体内，OA抑制了结肠癌异种移植小鼠的肿瘤生长。我们的结果表明，OA通过p38/FOXO3a/沉默调节蛋白6信号通路在结肠癌中同时诱导细胞凋亡和促生存的线粒体自噬。此外，我们的数据表明，OA可使结肠癌细胞对5-氟尿嘧啶（5-FU）产生化学敏感性。
