Inhibition of STAT3Y705 phosphorylation by Stattic suppresses proliferation and induces mitochondrial-dependent apoptosis in pancreatic cancer cells

Hangcheng Guo; Yanyi Xiao; Ziwei Yuan; Xuejia Yang; Jiawei Chen; Chaoyue Chen; Mengsi Wang; Lili Xie; Qinbo Chen; Yu Tong; Qiyu Zhang; Yongheng Bai

doi:10.1038/s41420-022-00922-9

Inhibition of STAT3^Y705 phosphorylation by Stattic suppresses proliferation and induces mitochondrial-dependent apoptosis in pancreatic cancer cells

Cell Death Discov. 2022 Mar 14;8(1):116. doi: 10.1038/s41420-022-00922-9.

Authors

Hangcheng Guo¹, Yanyi Xiao¹, Ziwei Yuan¹, Xuejia Yang¹, Jiawei Chen¹, Chaoyue Chen¹, Mengsi Wang¹, Lili Xie^{1

2}, Qinbo Chen¹, Yu Tong², Qiyu Zhang³, Yongheng Bai^{4

5}

Affiliations

¹ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
² Department of Laboratory Medicine, People's Hospital of Wenzhou City, Wenzhou, 325000, China.
³ Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. qiyu_zhang@wmu.edu.cn.
⁴ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. wzbyh@wmu.edu.cn.
⁵ Health Assessment Center, Wenzhou Medical University, Wenzhou, 325000, China. wzbyh@wmu.edu.cn.

Abstract

Patients with pancreatic cancer (PC) show dismal prognosis and high mortality. The development of PC is associated with the overactivation of STAT3. Here, we have determined that the non-peptide small molecule Stattic inhibits PC development by targeting STAT3. In vitro, Stattic treatment time- and dose-dependently inhibited proliferation of pancreatic cancer cells (PCCs) by reducing c-Myc expression and enhancing p53 activity. Consequently, p-Rb, cyclin D1, Chk1, and p21 (cell cycle proteins) were downregulated, and PCCs were arrested at the G1 phase, which was also confirmed by decreased Ki67 expression and unaltered PCNA expression. In addition, Stattic-induced mitochondrial-dependent apoptosis by elevating cleaved caspase-3, and Bax, cytochrome C levels, while reducing expression of Bcl-2, which may be regulated by reduced survivin expression. Further studies showed that Stattic exerts its anti-tumor effect via inhibition of STAT3^Y705 phosphorylation and nuclear localization in PCCs. In a nude mouse tumorigenesis model, Stattic inhibited PC growth by antagonizing STAT3^Y705 phosphorylation. Interleukin-6 used as a molecule agonist to activate STAT3, as well as overexpression of STAT3, could partially reverse Stattic-mediated anti-proliferation and pro-apoptotic effects of PCCs. Thus, these findings indicate that inhibition of STAT3^Y705 phosphorylation by Stattic suppresses PCC proliferation and promotes mitochondrial-mediated apoptosis.