Proteomics Reveal the Inhibitory Mechanism of Levodopa Against Esophageal Squamous Cell Carcinoma

Abstract

High recurrence rates and poor survival of patients with esophageal squamous cell carcinoma (ESCC) after treatment make ongoing research on chemoprevention drugs for ESCC particularly important. In this study, we screened a large number of FDA-approved drugs and found levodopa, a drug used to treat Parkinson's disease, had an inhibitory effect on the growth of ESCC cells. To elucidate the molecular mechanisms involved, we applied quantitative proteomics to investigate the anti-tumor activity of levodopa on ESCC. The results suggest that levodopa could down-regulate oxidative phosphorylation, non-alcoholic fatty liver disease, and Parkinson's disease pathways. Major mitochondrial respiratory compounds were involved in the pathways, including succinate dehydrogenase subunit D, NADH-ubiquinone oxidoreductase Fe-S protein 4, and mitochondrial cytochrome c oxidase subunit 3. Down-regulation of these proteins was associated with mitochondrial dysfunction. Western blotting and immunofluorescence results confirmed the proteomics findings. Cell viability assays indicated mitochondrial activity was suppressed after levodopa treatment. Reduced mitochondrial membrane potential was detected using JC-1 staining and TMRE assays. Transmission electron microscopy revealed changes in the morphology of mitochondria. Taken together, these results indicate that levodopa inhibited the growth of ESCC through restraining mitochondria function.

Inhibitory Mechanism of Combined Hydroxychavicol With Epigallocatechin-3-Gallate Against Glioma Cancer Cell Lines: A Transcriptomic Analysis

“…On a similar note, MT-CO3 (down regulated in this study), also involved in the metabolism process specifically the oxidative phosphorylation, influence abnormal energy metabolism and facilitate the growth of tumor cells. Levodopa was shown to inhibit the proliferation of esophageal squamous cell carcinoma (ESCC) via down-regulating the levels of oxidative phosphorylation proteins which includes MT-CO3, SDHD and NDUFS4 ( Li et al, 2020 ). This inhibition is related to mitochondrial dysfunction.…”

Identification of differentially expressed proteins in the locoregional recurrent esophageal squamous cell carcinoma by quantitative proteomics

“…Up to date, proteomics have been widely used to investigate therapeutic efficacy and mechanism of action of drugs. Li et al (31) applied quantitative proteomics to investigate the anti-tumor activity of levodopa on ESCC to the molecular mechanisms. Using comparative proteomic to screen DEPs between KYSE150 cells treated with 600 μM levodopa and untreated KYSE150 cells, they found levodopa could down regulate oxidative phosphorylation, non-alcoholic fatty liver disease, and Parkinson's disease pathways.…”

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“…A p < 0.05 was significant. Specific experimental methods were conducted according to our previous research 21,22 …”