MLL3 Induced by Luteolin Causes Apoptosis in Tamoxifen-Resistant Breast Cancer Cells through H3K4 Monomethylation and Suppression of the PI3K/AKT/mTOR Pathway.

Wu, Han-Tsang; Liu, Yi-En; Hsu, Kai-Wen; Wang, Yu-Fen; Chan, Ya-Chi; Chen, Yeh; Chen, Dar-Ren

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.

CELL proliferation; APOPTOSIS; BREAST tumors; CELL culture; CELL cycle; CELL lines; CELL surface antigens; CELLULAR signal transduction; DRUG resistance in cancer cells; ENZYME-linked immunosorbent assay; IMMUNODIAGNOSIS; LEUKEMIA; MEMBRANE proteins; MITOCHONDRIA; MOLECULAR structure; POLYMERASE chain reaction; RESEARCH funding; TAMOXIFEN; WESTERN immunoblotting; WOUND healing; DATA analysis software; FLAVONES; PROTEIN kinase inhibitors; DESCRIPTIVE statistics

American Journal of Chinese Medicine, 2020, Vol 48, Issue 5, p1221

0192-415X

Academic Journal

10.1142/S0192415X20500603