Related Experiment Video
Updated: May 9, 2025
Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
Published on: January 31, 2025
The ester derivative Palmitoylcarnitine abrogates cervical cancer cell survival by enhancing lipotoxicity and
Sangavi Eswaran1, Roshan Mascarenhas2,3, Shama Prasada Kabekkodu4
1Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Background:
In cervical cancer (CC), Double C2 Like Domain Beta (DOC2B) functions as a metastatic suppressor. The present study aims to determine whether ectopic expression of DOC2B causes global metabolomic changes in extracellular vesicles (EVs) and corresponds with its tumor suppressive properties.
Methods:
Using a retroviral method, we first ectopically expressed DOC2B in SiHa cells, which do not normally express DOC2B.
Results:
We observed that ectopically expressed DOC2B significantly altered the global metabolite profile of EVs. Metabolomics identified significant enrichment of palmitoylcarnitine (PC) in EVs upon ectopic expression of DOC2B. We identified that SiHa and HeLa cells exhibited greater cytotoxicity to PC than gingival fibroblast, HaCaT, Cal27, and MCF7. PC treatment reduced the growth, proliferation, and migration of SiHa and HeLa cells, via increasing apoptosis and decreasing S-Phase cells. PC treatment resulted in morphological alterations, decreased length and number of filopodia, and expression of proteins related to cell cycle progression, proliferation, and the epithelial-to-mesenchymal transition. Further, PC treatment caused mitochondrial morphological changes, increased mitochondrial membrane potential, and decreased mtDNA content. The decreased GSH activity, glucose consumption rate, and lactate production upon PC treatment suggest that PC can induce metabolic reprogramming in CC cells. Increased oxidative stress, calcium overload, lipid droplet accumulation, mitochondrial lipotoxicity, and mitophagy suggest that PC can cause mitochondrial dysfunction. N-acetyl cysteine (NAC) treatment reversed the cytotoxic effect of PC, via decreasing lipid peroxidation rate and increasing GSH activity. PC treatment enhanced the cytotoxic effect of cisplatin in CC.
Conclusion:
DOC2B restoration or the use of PC may be employed as a novel therapeutic approach for CC.
Insights
Restoring Double C2 Like Domain Beta (DOC2B) in cervical cancer cells altered extracellular vesicle metabolites, enriching palmitoylcarnitine (PC). PC demonstrated potent anti-cancer effects, inhibiting growth and migration, suggesting a novel therapeutic strategy.
Area of Science:
- Oncology
- Metabolomics
- Cell Biology
Background:
- Double C2 Like Domain Beta (DOC2B) acts as a metastatic suppressor in cervical cancer (CC).
- The study investigates the impact of DOC2B expression on extracellular vesicle (EV) metabolomics and its correlation with tumor suppressive functions.
Purpose of the Study:
- To determine if ectopic DOC2B expression induces global metabolomic changes in EVs.
- To correlate these metabolomic alterations with the known tumor suppressive properties of DOC2B.
Main Methods:
- DOC2B was ectopically expressed in SiHa cervical cancer cells using a retroviral method.
- Global metabolomic profiling of EVs was performed.
- Cytotoxicity assays, cell proliferation, migration, apoptosis, and mitochondrial function assays were conducted using palmitoylcarnitine (PC).
Main Results:
- Ectopic DOC2B expression significantly altered the EV metabolite profile, notably enriching palmitoylcarnitine (PC).
- PC exhibited significant cytotoxicity towards SiHa and HeLa CC cells, reducing proliferation, migration, and inducing apoptosis.
- PC induced mitochondrial dysfunction, metabolic reprogramming, and enhanced cisplatin cytotoxicity in CC cells.
Conclusions:
- DOC2B restoration alters EV metabolomics, leading to the enrichment of the anti-cancer metabolite PC.
- PC demonstrates significant anti-cancer properties and can enhance chemotherapy efficacy.
- Both DOC2B restoration and PC application represent potential novel therapeutic strategies for cervical cancer.
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