Abstract
BackgroundShikonin (SKO) is a natural naphthoquinone derived from Chinese herbal medicine Arnebiae Radix with high development potentials due to its anti-inflammatory and anti-tumor activities. Overwhelming evidences have indicated that SKO can induce both necrosis and apoptosis in cancer cells, while the mechanisms for triple negative breast cancer cells is still need to be disclosed.MethodsIn this study, kinds of molecular biological technologies, including flow-cytometry, Western blot, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA) as well as real-time quantitative PCR (RT-qPCR), were applied for investigation on the underlying mechanisms of SKO induced necrosis and apoptosis for MDA-MB-231 cells. Inhibitors were also used for validation ofthe key signaling pathways involved in SKO triggered necrosis and apoptosis.ResultsWe found that SKO significantly triggered necrosis and apoptosis of MDA-MB-231 cells in both a concentration- and time-dependent manner. Mechanism studies demonstrated that SKO significantly promoted the autoubiquitination levels and facilitated the proteasome dependent degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and cIAP2 in MDA-MB-231 cells. Autoubiquitination and degradation of cIAP1 and cIAP2 induced by SKO further led to significant decreased ubiquitination and inactivation of RIP1, which played an important role in inhibition of pro-survival and accelerating of necrosis of MDA-MB-231 cells. Treatment with proteasome inhibitor lactacystin significantly rescued the cell viability induced by treatment of SKO.ConclusionsOur results demonstrate that SKO promotes the autoubiquitination and degradation of cIAP1 and cIAP2, which further induces the decrease of the ubiquitination of RIP1 to inhibit the activation of pro-survival signaling pathways and accelerate the necrosis of MDA-MB-231 cells. The disclosed mechanisms of SKO induced necrosis and apoptosis in our study is firstly reported, and it is believed that SKO could be considered as a potential candidate and further developed for the treatment of triple negative breast cancer.
Highlights
Shikonin (SKO) is a natural naphthoquinone derived from Chinese herbal medicine Arnebiae Radix with high development potentials due to its anti-inflammatory and anti-tumor activities
The relative cell viability was 49.2% when cells treated with 2.5 μM SKO for 12 h, and the relative cell viability was significantly increased to 68.5% by addition of 10 μM Nec-1. These results demonstrated that cells treatment with SKO lead to increase auto-ubiquitination and degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and cIAP2, and interfered ubiquitination and activation of receptor-interacting protein 1 (RIP1) in cells, which played a crucial role in regulation of cell necrosis and apoptosis depended on RIP1 activity
In triple negative breast cancer, we discovered the involvement of ubiquitination and degradation of cIAP1 and cIAP2 by SKO played a key role in cell necrosis and apoptosis (Fig. 3a, b)
Summary
Shikonin (SKO) is a natural naphthoquinone derived from Chinese herbal medicine Arnebiae Radix with high development potentials due to its anti-inflammatory and anti-tumor activities. Breast cancer accounts for one-tenth of all new diagnosed cancers worldwide every year [1]. It is the most common cancer among women in developing and developed regions and is becoming the leading cause of cancer. Breast cancer is presently considered as the most common cancer among Chinese women, which is occurred in most other countries [3]. Cases from China account for 12.2% of all newly diagnosed breast cancers and 9.6% of global breast cancer deaths [4]. The types of breast cancer range from simple histological types, tumor grade, lymph node status, and predictive markers such as estrogen receptors to more complex classifications based on human epidermal growth factor receptor 2 (HER2) [6]. The classification of breast cancer includes lumen A (Luminal A), lumen B, basal-like, HER2-positive and normal subgroups [7, 8]
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