Abstract
Increased lipogenesis and protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression and is under intense investigation as a potential antineoplastic target. Acetyltanshinone IIA (ATA) is a compound that was obtained from chemical modifications of tanshinone IIA (TIIA), a potent anticancer agent extracted from the dried roots of the Chinese herbal medicine Salvia miltiorrhiza Bunge. A previous investigation indicated that ATA is more effective in inhibiting the growth of breast cancer especially cells with HER2 overexpression. However, the molecular mechanism(s) mediating this cytotoxic effect on HER2-positive breast cancer remained undefined. Studies described here report that ATA induced G1/S phase arrest and apoptosis in the HER2-positive MDA-MB-453, SK-BR-3, and BT-474 breast cancer cell lines. Mechanistic investigations revealed that the ATA-induced apoptosis effect is associated with remarkably down-regulation of receptor tyrosine kinases (RTKs) EGFR/HER2 and inhibition of their downstream pro-survival signaling pathways. Interestingly, ATA was found to trigger oxidative and endoplasmic reticulum (ER) stresses and to activate AMP activated protein kinase (AMPK) leading to inactivation of key enzymes involved in lipid and protein biogenesis. Intraperitoneal administration of ATA significantly inhibited the growth of MDA-MB-453 xenografts in athymic mice without causing weight loss and any other side effects. Additionally, transwell migration, invasion, and wound healing assays revealed that ATA could suppress tumor angiogenesis in vitro. Taken together, our data suggest that ATA may have broad utility in the treatment of HER2-overexpressed breast cancers.
Highlights
Breast cancer is by far the most common noncutaneous malignancy affecting women worldwide
Acetyltanshinone IIA (ATA) mediated inhibition of cancer cell growth by inducing cell cycle arrest and apoptosis To determine the cause and the nature of cell death by which ATA mediated its cytotoxic effects on HER2positive breast cancer cells, cell cycle progression and apoptosis were examined by flow cytometry
We focused our investigation on acetyltanshinone IIA (ATA) which is described as a promising cytotoxic agent from herbal origin with potent in vitro and in vivo anticancer properties [36]
Summary
Breast cancer is by far the most common noncutaneous malignancy affecting women worldwide. Despite considerable progress in both diagnosis and treatment, breast cancer remains the second leading cause of cancer-related death in women [1, 2]. The importance of the human epidermal growth factor receptor (HER, known as ErbB) family in the development and progression of various cancers is widely recognized [3]. Members include four receptors: HER1 (EGFR/ ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) [4]. Each has been reported to be amplified or overexpressed in some forms of breast cancer, with www.impactjournals.com/oncotarget. Overexpression of HER2, found in more than 30% of breast cancer cases [5, 6], is associated with poor prognosis and considered as a predictive marker of chemoresistance. Therapeutic strategies focusing on the inhibition of this oncogene are being actively explored in breast cancer therapy
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