Enhanced Efficacy of Combined TM with Cisplatin Targeting Esophageal Squamous Cell Carcinoma Via Suppressing Stat3 Signaling Pathway

Ammonium tetrathiomolybdate (TM) has been verified to be tightly implicated in antitumor efficacy in a wide range of tumor types. Here, we found TM significantly suppressed tumor proliferation in vitro in esophageal squamous cell carcinoma (ESCC) cells. Besides, TM markedly arrested cell cycle in S phase, induced cell apoptosis and reduced cell migration and invasion ability in a variety of ESCC cells, which may be tightly associated with c-Abl downregulation in ESCC cells. Importantly, TM significantly enhanced the killing efficacy of cisplatin on ESCC cell lines, and TM combined with cisplatin obviously induced cell apoptosis and reduced invasive cell numbers in different ESCC cells. Most strikingly, TM combined with cisplatin evidently inactivated Stat3 signaling pathway in ESCC cells, but IL-6 abolished the inactivation of Stat3 signaling pathway triggered by TM/cisplatin in ESCC cells. As expected, Stat3 activation evoked by IL-6 significantly reversed anti-proliferation ability mediated by TM/cisplatin in ESCC cells. Furthermore, in vivo animal experiments revealed that TM/cisplatin markedly suppressed tumor growth, and stepwise investigation demonstrated that TM, cisplatin or TM/cisplatin significantly reduced the expressions of angiogenesis related factors including VEGF, CD31 and ERG-1 proteins as well as p-Stat3 level in xenografted nude mice tumors. Our current results presented herein suggest that TM may be an underlying antitumor drug for ESCC and a promising agent for improving cisplatin resistance in clinic, which may be at least in part achieved by inactivating Stat3 signaling pathway. Funding: This project was supported by the National Natural Science Foundation of China (81372677 and 81272691), the Natural Science Foundation of Henan Province (No. 182300410377), the Key Scientific Research Projects of Henan Higher Education Institutions (No.17A180016), the Foundation and Cutting-edge Technology Projects of Henan Province (No. 152300410052) and the High School Science and Technology Innovation Talents Project of Henan Province (No. 15HASTIT037). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: All procedures were conducted out according to protocols approved by the Institutional Committee for Use and Care of Laboratory Animals of Zhengzhou University.