Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasis in vitro and in vivo

Feng,Jinhong; Zheng,Ting; Hou,Zhaohua; Lv,Cui; Xue,Anqi; Han,Tingting; Han,Beibei; Sun,Xin; Wei,Yunbo

doi:10.3892/or.2020.7781

Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasis in vitro and in vivo

Authors:
- Jinhong Feng
- Ting Zheng
- Zhaohua Hou
- Cui Lv
- Anqi Xue
- Tingting Han
- Beibei Han
- Xin Sun
- Yunbo Wei
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Affiliations: Laboratory of Immunology for Environment and Health, School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250014, P.R. China, School of Food Science and Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250014, P.R. China
Published online on: September 25, 2020 https://doi.org/10.3892/or.2020.7781
Pages: 2231-2240

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Abstract

Estrogen receptor (ER)‑negative breast tumors are associated with low survival rates, which is related to their ability to grow and metastasize into distal organs. The aryl hydrocarbon receptor (AhR), a ligand‑activated transcription factor that is involved in several biological processes, is a promising anti‑metastatic target. Luteolin, a non‑toxic naturally occurring plant flavonoid with diverse biological activities, has been demonstrated to be effective against certain types of cancer, and has also been described as a ligand of AhR. In the present study, various cancer cell lines were first investigated following treatment with luteolin, and luteolin exhibited the lowest IC50 in MDA‑MB‑231 cells. Then, the efficiency of luteolin in suppressing the metastasis of ER‑negative breast cancer in vitro was assessed. MDA‑MB‑231 cells were treated with luteolin in vitro. Subsequently, MTT assay and flow cytometry were used to detect cell viability, the cell cycle and apoptosis, and a Transwell assay was used to evaluate cell invasion. In addition, reverse transcription‑semi‑quantitative PCR and western blot were performed to detect the mRNA and protein expression levels of matrix metalloproteinase (MMP)‑2 and MMP‑9. In addition, the number of surface tumor nodules was measured in vivo, in mice bearing B16‑F10 tumors, following treatment with luteolin. Luteolin inhibited the viability and induced the apoptosis of MDA‑MB‑231 cells, which was accompanied by cell cycle arrest. This was associated with a decrease in the expression of the pro‑metastatic markers C‑X‑C chemokine receptor type 4 (CXCR4), MMP‑2 and MMP‑9, which was reversed by AhR inhibition. Furthermore, it was identified that luteolin could inhibit the metastasis in a B16F10 mouse xenograft model, and the levels of MMP‑9, MMP‑2 and CXCR4 were significantly decreased in the lung tissues isolated from tumor‑bearing nude mice following luteolin treatment. In conclusion, luteolin is a potential molecule for inhibiting breast cancer invasion and metastasis, which could have promising clinical applications.

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