Abstract
Background/AimNobiletin 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 MethodsWe 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.ResultsNobiletin 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.ConclusionsNobiletin 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.
Highlights
Since PKA/CREB activity is directly associated with mitochondrial activity (Xie et al, 2018), we evaluated the mitochondrial activity of oral squamous cell carcinoma (OSCC) cells treated with nobiletin
MitoTracker Green staining showed that nobiletin treatment resulted in less alive and metabolically active mitochondria and administration of Sp-cAMP rescued the number of functional mitochondria (Figure 3b) suggesting that nobiletin reduced the mitochondrial number and inhibited their activity in OSCC cells
Our data showed that nobiletin alone was able to restrain the growth of OSCC cells through inducing
Summary
1 × 106 TCA-8113 cells treated with 100 μmol/L nobiletin with or without 50 μmol/L Sp-cAMP were harvested and homogenized in pyruvate assay buffer. (b) TCA-8113 and CAL-27 cells were treated with 100 μmol/L nobiletin for 24 hr in the absence or presence of 50 μmol/L Sp-cAMP, a potent PKA activator, followed by Western blot analysis of proliferation-related proteins. Our results showed that nobiletin treatment of TCA-8113 and CAL-27 cells resulted in a dose-dependent decrease in the levels of PKA and phosphorylated-PKA (Figure 2a).
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