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Oleanolic acid induces cytoprotective mitophagy in HCT116 human colon carcinoma cells

Colorectal cancer is a disease that occupies a very high place in terms of its malignancy and mortality. Therefore, it is of high importance to discover compounds that can efficiently ameliorate the disease and reduce mortality. Oleanolic acid (OA), a natural triterpene compound, has been shown to possess beneficial health effects, including anticancer activity. However, the effect of OA on mitophagy in colon cancer cells is unknown. The aim of this study was to investigate the mechanism and the role of autophagy/mitophagy in the anticancer activity of OA in HCT116 human colon carcinoma cells, cell line commonly used in colon cancer studies, and therapeutic drug development. Additionally, we examined chemosensitization to 5­fluorouracil (5­FU). OA dose­dependently reduced viability of HCT116 cells, with IC50 = 29.8 µM. The expression of cleaved caspase­3 and poly (ADP­ribose) polymerase 1 (PARP) increased by OA treatment, suggesting that OA induces apoptosis in HCT116 cells. OA induced autophagy in cancer cells by increasing expression of Beclin­1, Atg5 and microtubule­associated protein 1A/1B­light chain 3 beta­II (LC3B­II), which was found to be protective. Induction of mitophagy was suggested by increased expression of p62 and PTEN­induced kinase 1 (PINK1) and reduced expression of translocase of outer mitochondrial membrane 20 (TOMM20), which colocalized with LC3B. OA induced nuclear accumulation of forkhead box O3a (FOXO3a) and phosho­FOXO3a. The cytotoxic activity of OA coincided by suppression of the phosphoinositide 3­kinase (PI3K)/Akt and extracellular regulated kinase 1/2 (ERK1/2) pathways and activation of AMP­activated protein kinase (AMPK), c­Jun N­terminal kinase 1 (JNK1), and p38. The results of the study show the cytotoxic activity of OA in HCT116 human colon carcinoma cells with concomitant induction of survival autophagy and mitophagy through modulation of key signaling pathways. Moreover, OA chemosensitized HCT116 cells to 5­FU.

oleanolic acid, HCT116 human colon cancer cells, apoptosis, autophagy, mitophagy, 5-Fluorouracil

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