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Mitochondrial dysfunction is responsible for fatty acid synthase inhibition-induced apoptosis in breast cancer cells
Qiang Wang1, Xia Du1, Bingjie Zhou1
1School of Pharmacy, Jiangsu University, Zhenjiang, 212013, China.
Abstract:
Targeting cellular metabolism is becoming a hallmark to overcome drug resistance in breast cancer treatment. Activation of fatty acid synthase (FASN) has been shown to promote breast cancer cell growth. However, there is no concrete report underlying the mechanism associated with mitochondrial dysfunction in relation to fatty acid synthase inhibition-induced apoptosis in breast cancer cells. The current study is aimed at exploring the effect of the novel manganese (Mn) complex, labeled as PdpaMn, on lipid metabolism and mitochondrial function in breast cancer cells. Herein, we observed that PdpaMn displayed strong cytotoxicity on breast cancer cell lines and selectively targeted the tumor without affecting the normal organs or cells in vivo. We also observed that PdpaMn could bind to TE domain of FASN and decrease the activity and the level of expression of FASN, which is an indication that FASN could serve as a target of PdpaMn. In addition, we demonstrated that PdpaMn increased intrinsic apoptosis in breast cancer cells relayed by a suppressed the level of expression of FASN, followed by the release of mitochondrial cytochrome c and the activation of caspases-9. Instigated by the above observations, we hypothesized that PdpaMn-induced apoptosis events are dependent on mitochondrial dysfunction. Indeed, we found that mitochondrial membrane potential (MMP) collapse, mitochondrial oxygen consumption reduction and adenosine triphosphate (ATP) release were deeply repressed. Furthermore, our results showed that PdpaMn significantly increased the reactive oxygen species (ROS) production, and the protection conferred by the free radical scavenger N-acetyl-cysteine (NAC) indicates that PdpaMn-induced apoptosis through an oxidative stress-associated mechanism. More so, the above results have demonstrated that mitochondrial dysfunction participated in FASN inhibition-induce apoptosis in breast cancer cells by PdpaMn. Therefore, PdpaMn may be considered as a good candidate for anti-breast cancer therapeutic option.
Insights
A novel manganese complex, PdpaMn, effectively targets fatty acid synthase (FASN) in breast cancer cells, inducing apoptosis via mitochondrial dysfunction and oxidative stress. This compound shows promise as a new therapeutic option for breast cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Targeting cellular metabolism is crucial for overcoming drug resistance in breast cancer.
- Fatty acid synthase (FASN) activation promotes breast cancer cell growth, but its role in FASN inhibition-induced apoptosis via mitochondrial dysfunction remains unclear.
Purpose of the Study:
- To investigate the effects of a novel manganese (Mn) complex, PdpaMn, on lipid metabolism and mitochondrial function in breast cancer cells.
- To elucidate the mechanism of PdpaMn-induced apoptosis in breast cancer.
Main Methods:
- Cytotoxicity assays on breast cancer cell lines and in vivo tumor targeting studies.
- Assessment of FASN activity, expression levels, and binding.
- Analysis of intrinsic apoptosis markers (cytochrome c release, caspase-9 activation).
- Evaluation of mitochondrial function (membrane potential, oxygen consumption, ATP release).
- Measurement of reactive oxygen species (ROS) production and assessment of oxidative stress using N-acetyl-cysteine (NAC).
Main Results:
- PdpaMn exhibited significant cytotoxicity against breast cancer cells and selective tumor targeting in vivo.
- PdpaMn inhibited FASN activity and expression by binding to its TE domain.
- PdpaMn induced intrinsic apoptosis, characterized by FASN suppression, cytochrome c release, and caspase-9 activation.
- Mitochondrial dysfunction, including reduced membrane potential, oxygen consumption, and ATP release, was observed.
- PdpaMn increased ROS production, indicating an oxidative stress-associated apoptotic mechanism.
Conclusions:
- PdpaMn effectively inhibits FASN and induces apoptosis in breast cancer cells through mitochondrial dysfunction and oxidative stress.
- The novel Mn complex PdpaMn demonstrates potential as a therapeutic agent for breast cancer.