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Oleanolic acid induces HCT116 colon cancer cell death through the p38/FOXO3a/Sirt6 pathway
Iva Potočnjak1, Lidija Šimić1, Iva Vukelić1
1Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Croatia.
Abstract:
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 IC50 = 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).
Insights
Oleanolic acid (OA) triggers apoptosis and mitophagy in colon cancer cells, inhibiting tumor growth. It also enhances the effectiveness of 5-fluorouracil (5-FU) chemotherapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Oleanolic acid (OA), a natural compound, exhibits anticancer properties.
- The role of forkhead box O3a (FOXO3a) in OA-induced autophagy and mitophagy in colon cancer remains to be elucidated.
Purpose of the Study:
- To investigate the role of FOXO3a in OA-induced autophagy and mitophagy in the HCT116 colon cancer cell line.
- To explore the underlying signaling pathways involved in OA's anticancer effects.
Main Methods:
- Cell viability assays (IC50 determination).
- Western blotting to assess apoptosis markers (cleaved caspase-3, PARP1) and autophagy/mitophagy markers (Beclin-1, ATG5, LC3B, p62, PINK1, TOMM20).
- Immunofluorescence for LC3B colocalization.
- Analysis of FOXO3a nuclear accumulation and p38 MAPK pathway.
- In vivo studies using colon cancer xenograft mouse models.
- Assessment of OA's effect on 5-fluorouracil (5-FU) chemosensitivity.
Main Results:
- OA dose-dependently reduced HCT116 cell viability and induced apoptosis.
- OA triggered autophagy and mitophagy, indicated by altered expression of key proteins and LC3B colocalization with mitochondrial markers.
- OA induced nuclear accumulation of FOXO3a and upregulated p38.
- Inhibition of p38 increased FOXO3a and Sirtuin 6 (Sirt6) expression.
- OA suppressed tumor growth in vivo and enhanced 5-FU efficacy.
Conclusions:
- OA induces apoptosis and prosurvival mitophagy in colon cancer cells via the p38/FOXO3a/Sirt6 signaling pathway.
- OA demonstrates potential as an anticancer agent and a chemosensitizer for colon cancer treatment.
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