Abstract
Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.
Highlights
Oral squamous cell carcinoma (OSCC), a malignancy that arises from the epithelial mucosa of the oral cavity, is a public health problem worldwide
As a critical kinase responsible for cell cycle progression and G2/M transition, Aurora B is frequently overexpressed in human cancer cells and closely related to poor prognosis[9]
In small cell lung cancer (SCLC), Aurora B is required for the survival of RB1-deficient cancer cells[23]
Summary
Oral squamous cell carcinoma (OSCC), a malignancy that arises from the epithelial mucosa of the oral cavity, is a public health problem worldwide. The incidence and mortality of OSCC have been increased over the past few decades, and over 95% of people with OSCC smoke tobacco, drink alcohol, and chew betel nut[1,2]. For most OSCC early cases, surgery is the initial treatment of choice. OSCC is frequently diagnosed at an advanced stage, and postoperative radiation or chemoradiation is needed if the disease has high-risk features. The distant metastasis remains the major reason to cause relapse and therapy failure, and the 5-year overall survival (OS) of OSCC patients was less than 50%3–5. Further elucidate the underlying mechanism of OSCC oncogenesis, and the discovery of critical drivers are the major challenges for OSCC treatment
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