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Published on: January 31, 2025
Oleanolic acid induces protective autophagy in cancer cells through the JNK and mTOR pathways
Jia Liu1, Lanhong Zheng2, Jiateng Zhong3
1Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, Shandong 266071, P.R. China.
Abstract:
Autophagy is a biological process that eliminates damaged or excessive proteins and is utilized by various types of cells to maintain cellular homeostasis. Autophagy also occurs in cancer cells and exerts anti-survival or pro-survival effects depending on stimuli, nutrient and context. Oleanolic acid (OA), a widely spread natural compound, induces apoptosis in a range of cancer cells. However, some tumor cell lines are resistant to the pro-apoptotic effect of OA, and the mechanism remains unknown. In the present study, we found that OA induced autophagic event in cancer cells in a dose- and time-dependent manner, evidenced by an increased ratio between LC3-II and LC3-I and frequent granulation of LC3 proteins in OA-stimulated tumor cell lines. Inhibition of autophagy potentiated the pro-apoptotic activity of OA on cancer cells. Furthermore, the JNK and mTOR signaling pathways were found to be affected by OA treatment. Interfering with JNK and mTOR abolished OA-induced autophagy and sensitized cancer cells to apoptosis. Collectively, we showed that OA was able to initiate protective autophagy, which compromised the antitumor activity of OA on cancer cells. Blocking autophagy may be a promising strategy to enhance the tumor suppressor activity of OA.
Insights
Oleanolic acid (OA) triggers protective autophagy in cancer cells, hindering its tumor-killing effects. Blocking this autophagy enhances OA's cancer-fighting potential, suggesting a new therapeutic strategy.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Autophagy is a cellular process for protein degradation crucial for homeostasis.
- Cancer cells utilize autophagy, which can promote or inhibit survival depending on context.
- Oleanolic acid (OA) induces apoptosis in cancer cells, but resistance mechanisms are unclear.
Purpose of the Study:
- To investigate the role of autophagy in cancer cell resistance to Oleanolic acid (OA).
- To explore the signaling pathways involved in OA-induced autophagy.
- To determine if inhibiting autophagy can enhance OA's anti-cancer effects.
Main Methods:
- Assessing autophagy markers (LC3-II/LC3-I ratio, LC3 granulation) in OA-treated cancer cells.
- Evaluating the effect of autophagy inhibition on OA-induced apoptosis.
- Analyzing the involvement of JNK and mTOR signaling pathways in OA response.
Main Results:
- OA dose- and time-dependently induced autophagy in cancer cells.
- Inhibiting autophagy potentiated OA's pro-apoptotic activity.
- OA affected JNK and mTOR signaling, and interfering with these pathways modulated autophagy and apoptosis.
Conclusions:
- OA induces protective autophagy in cancer cells, which counteracts its anti-tumor effects.
- Blocking autophagy enhances the tumor suppressor activity of OA.
- Targeting autophagy represents a potential strategy to improve OA-based cancer therapy.
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