Abstract
Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicinal herb, which exerts anticancer effects in various cancers. However, the molecular mechanisms underlying the therapeutic effects of shikonin against endometrioid endometrial cancer (EEC) have not yet been fully elucidated. Herein, we investigated anticancer effects of shikonin on EEC cells and explored the underlying molecular mechanism. We observed that shikonin inhibits proliferation in human EEC cell lines in a dose-dependent manner. Moreover, shikonin-induced apoptosis was characterized by the up-regulation of the pro-apoptotic proteins cleaved-Caspase-3 and Bax, and the down-regulation of the anti-apoptotic protein Bcl-2. Microarray analyses demonstrated that shikonin induces many miRNAs’ dysregulation, and miR-106b was one of the miRNAs being most significantly down-regulated. miR-106b was identified to exert procancer effect in various cancers, but in EEC remains unclear. We first confirmed that miR-106b is up-regulated in EEC tissues and cells, and knockdown of miR-106b suppresses proliferation and promotes apoptosis. Meanwhile, our results validated that the restored expression of miR-106b abrogates the antiproliferative and pro-apoptotic effects of shikonin. We also identified that miR-106b targets phosphatase and tensin homolog (PTEN), a tumor suppressor gene, which in turn modulates AKT/mTOR signaling pathway. Our findings indicated that shikonin inhibits proliferation and promotes apoptosis in human EEC cells by modulating the miR-106b/PTEN/AKT/mTOR signaling pathway, suggesting shikonin could act a potential therapeutic agent in the EEC treatment.
Highlights
Endometrial cancer (EC) is the most common gynecologic malignancy in the developed countries [1]
To explore the antiproliferative effect of shikonin on endometrioid EC (EEC) cells, the human EEC cell lines Ishikawa, HEC-1A, KLE, and RL95-2 were treated with various concentrations of shikonin (0, 1, 2, 4, 8, 10, and 20 μM) for 24 h and the cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay
Our results showed that shikonin treatment markedly increased phosphatase and tensin homolog (PTEN) expression and decreased the p-AKT and p-mTOR levels compared with blank group in both Ishikawa and HEC-1A cells, but this shikonin-blocked PTEN/AKT/mTOR pathway was reactivated by overexpression of miR-106b (P
Summary
Endometrial cancer (EC) is the most common gynecologic malignancy in the developed countries [1]. Statistical analysis has shown that approximately 142000 women suffered from EC globally every year, and approximately 42000 women die from this disease [2] Amongst these EC cases, approximately 80% are endometrioid EC (EEC) [3], which is mainly treated with combination of surgery and adjuvant chemotherapy, radiotherapy or hormone therapy. An active naphthoquinone of Zi Cao, derived from the roots of the herb Lithospermu erythrorhizon that has been used in traditional Chinese medicine to treat skin diseases, burns and sore throats due to its antimicrobial and anti-inflammatory activities [5,6] It has been identified c 2018 The Author(s).
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