Biochemical and Biophysical Research Communications
Tivantinib (ARQ-197) exhibits anti-tumor activity with down-regulation of FAK in oral squamous cell carcinoma
Introduction
Oral cavity cancer, predominantly oral squamous cell carcinoma (OSCC), is one of the most common cancer in the world, with more than 300,000 new cases diagnosed in 2012 [1]. In the past decades, the five year survival rate of the OSCC patients still remains dismally low, only about 60% in the USA, despite the progression in surgery, chemotherapy and radiotherapy [2]. Acquired resistance to conventional chemotherapies and the metastasis have become serious obstacles for the OSCC treatment [3], [4].
Tivantinib (ARQ 197) was initially discovered as a non-ATP competitive MET inhibitor and exhibited effective in vitro and in vivo anti-tumor activities against many human cancers, such as gastric cancer, breast cancer, non-small-cell lung cancer (NSCLC), renal cancer and hepatocellular carcinoma (HCC) [5]. It has been reported that tivantinib might bind to the ATP-binding pocket and prevent MET auto-phosphorylation, which was the initial step for the completely activation of MET [6]. Inhibition of the auto-phosphorylation of MET by tivantinib could result in the suppression of the downstream pathway phosphorylation of AKT and ERK1/2 [5]. Meanwhile, Antonio Calles et al. showed that, compared to other MET inhibitors such as crizotinib and PHA-665752, the anti-proliferative activity of tivantinib was more potent and not restricted to only MET dependent NSCLC cell lines [7]. They also showed that tivantinib surprisingly did not inhibit cellular MET activation or phosphorylation of downstream signaling proteins AKT or ERK1/2 in either MET dependent or independent cell lines. Moreover, Aki Aoyama et al. demonstrated that tivantinib could directly bind to the colchicine binding site of tubulin and disrupt tubulin polymerization [8], [9], [10]. Recently, tivantinib was reported to bind and inhibit glycogen synthase kinase 3 (GSK3) alpha and beta in a greater degree than did MET [11]. These studies suggested that the anti-tumor mechanisms of tivantinib remain uncertain and need to be further illustrated [12]. Herein, we showed the anti-tumor effects of tivantinib on two OSCC cell lines, Cal27 and Tca8113, and probe into the potential underlying mechanisms.
Section snippets
Antibodies and reagents
Dulbecco's modified Eagle's medium (DMEM) and fetal bovine serum (FBS) were purchased from Thermo Scientific (South Logan, UT). Recombinant Human HGF was purchased from R&D Systems (Minneapolis, MN). MTT, propidium iodide (PI), RNase was purchased from Sigma–Aldrich (St Louis, MO). Gentian violet was purchased from Solarbio (Beijing, China). The Annexin VFICT/PI apoptosis detection kit were purchased from BD Biosciences (Franklin Lakes, NY). PVDF membrane and chemiluminescent reagents were from
Tivantinib suppresses cell growth and colony formation independent of the inhibition of HGF/MET signaling pathway in OSCC cells
The anti-proliferative effect of tivantinib was initially investigated on the two OSCC cell lines Cal27 and Tca8113. Cells were incubated with various concentrations (ranging from 0.031 to 1 μM) of tivantinib for 24, 48, and 72 h, and then the cell viability was determined using MTT assay. As shown in Fig. 1A, the treatment of cells with tivantinib resulted in the decreasing of cell viability in both dose- and time-dependent manner. The half maximal inhibitory concentration (IC50) values of
Discussion
Tivantinib is a promising oral available anti-cancer agent ongoing clinical trial. As monotherapy or combination with other agents, clinical studies showed that tivantinib exhibited encouraging antitumor activities, improved overall survival (OS) and progression-free survival (PFS) in NSCLC [20], advanced HCC [21] and metastatic gastric cancer patients [22]. However, up till now, its anti-tumor effect has not been evaluated in OSCC cells. Except for MET, tivantinib was subsequently found to
Conflict of interest
The authors have declared that no competing interests exist.
Acknowledgments
The study was supported by grants from National Natural Science Foundation of China (No. 81060087 and 81460410).
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W. Xi and L. Yang contributed equally to this work.