Nobiletin inhibits cell growth through restraining aerobic glycolysis via PKA-CREB pathway in oral squamous cell carcinoma

Background/aim: Nobiletin is a polymethoxylated flavone enriched in Citrus and is used as an important drug in traditional Chinese medicine for various kinds of diseases. Among its multiple functions, it has shown that nobiletin inhibits proliferation of various Cancer cells. However, it is unclear whether nobiletin inhibits the growth of oral squamous cell carcinoma (OSCC) cells.

Materials and methods: We explored the antitumor effects of nobiletin in TCA-8113 and CAL-27 oral squamous cells. The Cell Counting Kit-8 (CCK8) assay was used to measure cell vitality. Flow cytometry was performed to measure the number of cells in the various phases of the cell cycle. PCR and Western blot were applied to determine mRNA and protein expression, respectively.

Results: Nobiletin inhibited proliferation of TCA-8113 and CAL-27 cells via inducing cell cycle arrest at the G1 phase. In addition, the levels of phosphorylated-PKA and phosphorylated-CREB were reduced in nobiletin-treated TCA-8113 and CAL-27 cells. Importantly, our results showed that nobiletin treatment resulted in impaired mitochondrial function and altered glucose consumption, and pyruvate and lactate production. Lastly, nobiletin was found to inhibit the generation of xenografts in vivo. Interestingly, administration of 50 μmol/L Sp-cAMP, a potent PKA Activator, rescued all phenotypes caused by nobiletin.

Conclusions: Nobiletin inhibits OSCC cell proliferation in a mitochondria-dependent manner, indicating that it may have a promising role in Cancer treatment and attenuation of drug resistance.