nsc-74859 and Squamous-Cell-Carcinoma-of-Head-and-Neck

Autophagy is considered as a double-edged sword. It can prolong the survival of cancer cells and enhance its resistance to apoptosis, and paradoxically, defective autophagy has been linked to increased tumorigenesis, but the mechanism behind this phenomenon is unclear. In this study, we demonstrated that decreased phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) was correlated with increased autophagy through the Akt/mTOR and Erk signaling pathways in human head and neck squamous cell carcinoma (HNSCC). We also showed that blockage of STAT3 by NSC74859 could markedly induce apoptotic cell death and autophagy. Meanwhile, increased autophagy inhibited apoptosis. The pharmacological or genetic inhibition of autophagy and STAT3 further sensitized HNSCC cells to apoptosis. Furthermore, evidence from xenograft model proved that suppressed STAT3 activity combined with inhibition of autophagy promoted tumor regression better than either treatment alone. Taken together, this present study demonstrated that autophagy alleviates apoptotic cell death in HNSCC, and combination of inhibition of STAT3 by NSC74859 and autophagy might be a promising new therapeutic strategy for HNSCC.

Topics: Aminosalicylic Acids; Animals; Autophagy; Benzenesulfonates; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cluster Analysis; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Phosphorylation; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor; Tissue Array Analysis; Xenograft Model Antitumor Assays

Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.

Topics: 5'-Nucleotidase; Adenosine; Animals; Carcinoma, Squamous Cell; Cell Differentiation; Head and Neck Neoplasms; Mice; Mice, Inbred C3H; Monocytes; Mouth Neoplasms; Myeloid-Derived Suppressor Cells; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment

Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC.

Topics: Aminosalicylic Acids; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Self Renewal; Cell Survival; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Fluorouracil; Head and Neck Neoplasms; Humans; Mice, Knockout; Mice, Nude; Neoplastic Stem Cells; Phenotype; Phosphorylation; Side-Population Cells; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor; Taxoids; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays