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

Abstract

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.

• Authors: Han-Tsang Wu, Yi-En Liu, Kai-Wen Hsu, Yu-Fen Wang, Ya-Chi Chan, Yeh Chen, Dar-Ren Chen
• Journal: The American journal of Chinese medicine (Am J Chin Med) Vol. 48 Issue 5 Pg. 1221-1241 ( 2020) ISSN: 1793-6853 [Electronic] Singapore
• PMID: 32668964 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• DNA-Binding Proteins
• KMT2C protein, human
• Tamoxifen
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• ras Proteins
• Luteolin

Topics

• Antineoplastic Agents, Phytogenic
• Apoptosis (drug effects, genetics)
• Breast Neoplasms (genetics, pathology)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics, physiology)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression (drug effects)
• Humans
• Luteolin (pharmacology)
• Methylation (drug effects)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases
• Tamoxifen (pharmacology)
• ras Proteins (genetics, metabolism)