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CDDO-Me triggers ROS-dependent ferroptosis and apoptosis in cervical cancer via targeting PI3K/Nrf2 pathway
Wenxuan Li1, Mengying Wang1, Pan Du1
1Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, PR China.
Context:
Cervical cancer (CC) ranks as one of the most common types of malignant tumors affecting women. CDDO-Me is derived from oleanolic acid, a pentacyclic triterpenoid obtained by chemical structural modification, which has been shown anti-tumor effects.
Results:
CC cell proliferation was decreased by CDDO-Me both in vitro and in vivo. Mechanistically, CDDO-Me led to a reduction of intracellular mitochondrial volume and crista, or an increase of membrane density. The levels of ROS, Fe2+, MDA were increased while GSH was decreased. Meanwhile, the levels of protein expression of GPX4, Nrf2, NQO1 and FTH1 were observably inhibited by CDDO-Me. Specifically, ferroptosis triggered by CDDO-Me was reverted by DFO. It has been demonstrated that CDDO-Me-induced apoptosis and ferroptosis in CC cells is contingent upon the PI3K/AKT-mediated Nrf2/NQO1 pathway.
Conclusions:
CDDO-Me induces CC cell lines apoptosis and ferroptosis through the PI3K/Nrf2 signaling pathway, for exerting anti-proliferation effects.
Insights
CDDO-Me, a modified oleanolic acid derivative, effectively reduces cervical cancer cell proliferation by inducing apoptosis and ferroptosis. This occurs via the PI3K/Nrf2 signaling pathway, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cervical cancer (CC) is a prevalent malignancy in women.
- CDDO-Me, a chemically modified pentacyclic triterpenoid derived from oleanolic acid, exhibits demonstrated anti-tumor properties.
Purpose of the Study:
- To investigate the anti-proliferative effects of CDDO-Me on cervical cancer cells.
- To elucidate the underlying molecular mechanisms, including apoptosis and ferroptosis, involved in CDDO-Me's anti-cancer activity.
Main Methods:
- In vitro and in vivo studies were conducted using cervical cancer cell models.
- Mitochondrial morphology, reactive oxygen species (ROS), lipid peroxidation (MDA), and glutathione (GSH) levels were assessed.
- Protein expression of key regulators such as GPX4, Nrf2, NQO1, and FTH1 was analyzed.
- The role of the PI3K/AKT/Nrf2/NQO1 pathway was investigated, and ferroptosis was confirmed using DFO.
Main Results:
- CDDO-Me significantly decreased cervical cancer cell proliferation both in vitro and in vivo.
- Mechanistic studies revealed alterations in mitochondrial structure, increased ROS and MDA, and decreased GSH.
- CDDO-Me inhibited the expression of GPX4, Nrf2, NQO1, and FTH1, indicating ferroptosis induction.
- Apoptosis and ferroptosis induced by CDDO-Me were dependent on the PI3K/AKT-mediated Nrf2/NQO1 pathway.
Conclusions:
- CDDO-Me effectively induces apoptosis and ferroptosis in cervical cancer cell lines.
- The anti-proliferative effect of CDDO-Me is mediated through the PI3K/Nrf2 signaling pathway.
- CDDO-Me presents a promising therapeutic agent for cervical cancer treatment.
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