Journal
AMERICAN JOURNAL OF CHINESE MEDICINE
Volume 48, Issue 5, Pages 1221-1241Publisher
WORLD SCIENTIFIC PUBL CO PTE LTD
DOI: 10.1142/S0192415X20500603
Keywords
Breast Cancer; Estrogen Receptor; Drug Resistance; Luteolin; MLL3; H3K4 mel
Funding
- Ministry of Science and Technology Summit grant [MOST 108-2314-B-371]
- Department of Cell and Tissue Engineering, Changhua Christian Hospital [107-CCHNPI-053, 108-CCH-IRP-016]
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Tamoxifen is one of the most common hormone therapy drug for estrogen receptor (ER)-positive breast cancer. Tumor cells with drug resistance often cause recurrence and metastasis in cancer patients. Luteolin is a natural compound found from various types of vegetables and exhibit anticancer activity in different cancers. This study demonstrated that luteolin inhibits the proliferation and induces apoptosis of tamoxifen-resistant ER-positive breast cancer cells. Luteolin also causes cell cycle arrest at the G2/M phase and decreases mitochondrial membrane potential. Besides, luteolin reduces the levels of activated PI3K/AKT/mTOR signaling pathway. The combination treatment of luteolin and PI3K, AKT, or mTOR inhibitors synergistically increases apoptosis in tamoxifen-resistant ER-positive breast cancer cells. Ras gene family (K-Ras, H-Ras, and N-Ras), an activator of PI3K, was transcriptionally repressed by luteolin via induction of tumor suppressor mixed-lineage leukemia 3 (MLL3) expression. MLL3 increases the level of monomethylation of Histone 3 Lysine 4 on the enhancer and promoter region of Ras genes, thus causes repression of Ras expressions. Our finding implies that luteolin was a promising natural agent against tamoxifen resistance of breast cancer.
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