Intracellular reduction in ATP levels contributes to CYT 997‐induced suppression of metastasis of head and neck squamous carcinoma

The incidence rate of head and neck squamous cell carcinoma ( HNSCC ) has steadily increased over the past decade. However, treatment options for metastatic HNSCC are often limited and the 5‐year survival rate has remained static. Therefore, the development and assessment of more efficient but less toxic therapeutic strategies is an unmet need for treatment of more extensive HNSCC . Here, we report that CYT 997, a novel microtubule‐disrupting agent, exerts strong activity in inhibiting HNSCC cell invasion and metastasis. The loss of invasion capacity by CYT 997 was accompanied by an associated increase in cell adhesion and the reversal of epithelial‐mesenchymal transition ( EMT ). Increased expression of E‐cadherin protein and decreased expression of Vimentin protein became evident in HNSCC cells following CYT 997 exposure, which were consistently observed in HNSCC xenografts from the mice receiving CYT 997. Moreover, the capacity of invasive HNSCC cells to form pulmonary metastases was significantly blocked with CYT 997 treatment, indicating that the diminishment of EMT traits contributes to CYT 997‐suppressed metastasis. Intriguingly, CYT 997 impaired intracellular ATP levels in HNSCC cells, at least in part, through its inhibitory effect on the mitochondrial protein IF 1. The addition of ATP attenuated CYT 997‐induced suppression of cell invasion, coupled with down‐regulation of E‐Cadherin and up‐regulation of Vimentin. These findings support a critical role of ATP levels in cell invasion and metastasis under the influence of CYT 997. Collectively, our data unveil the mechanism involved in mediating CYT 997 action, and provide preclinical rationale for possible clinical application of CYT 997 as a novel therapeutic strategy against aggressive HNSCC .