Induction of estrogen receptor β-mediated autophagy sensitizes breast cancer cells to TAD1822-7, a novel biphenyl urea taspine derivative

Background Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) can be potentially targeted for breast cancer therapy. Methods and results TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferat...

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Bibliographic Details
Published in:	Molecular biology reports 2022-02, Vol.49 (2), p.1223-1232
Main Authors:	Su, Qi, Wu, Qing, Chen, Kun, Wang, Jingjing, Sarwar, Ammar, Zhang, Yanmin
Format:	Article
Language:	eng
Subjects:	1-Phosphatidylinositol 3-kinase AKT protein Alkaloids Animal Anatomy Animal Biochemistry Annexin V Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects Autophagy - physiology Biomedical and Life Sciences Biphenyl Compounds Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Cell culture Cell death Cell Hypoxia - drug effects Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Estrogen Receptor beta - metabolism Estrogen Receptor beta - physiology Estrogen receptors Estrogens Female Histology Humans Hypoxia Immunofluorescence Kinases Life Sciences Mitochondria Morpholines - metabolism Morpholines - pharmacology Morphology Original Article Phagocytosis Phenylurea Compounds - metabolism Phenylurea Compounds - pharmacology Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Signal Transduction - drug effects siRNA Transfection Tumor suppressor genes Tumors Urea Western blotting
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Summary:	Background Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) can be potentially targeted for breast cancer therapy. Methods and results TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting, ERβ siRNA, ERβ plasmid transfection and hypoxia cell models. TAD1822-7 upregulated ERβ causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERβ. Enhanced levels of microtubule associated protein1 light chain 3 (LC3)-II and p62/SQSTM1 (p62) indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, TAD1822-7 modulated hypoxia inducible factor (HIF) functions and autophagy via the inhibition of HIF-1β in the context of hypoxia-induced autophagy. ERβ overexpression and ERβ agonist showed similar effects, whereas ERβ siRNA abrogated TAD1822-7-induced cell death, the inhibition of PI3K/AKT pathway and autophagy. The involvement of PI3K/AKT pathway and autophagy was also demonstrated in TAD1822-7-treated hypoxic breast cancer cells. Conclusions These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERβ-mediated pathways in breast cancer cells.
ISSN:	0301-4851 1573-4978