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

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

doi:10.1038/s41420-022-00922-9

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 STAT3Y705 phosphorylation and nuclear localization in PCCs. In a nude mouse tumorigenesis model, Stattic inhibited PC growth by antagonizing STAT3Y705 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 STAT3Y705 phosphorylation by Stattic suppresses PCC proliferation and promotes mitochondrial-mediated apoptosis.

Highlights

Pancreatic cancer (PC) is generally associated with poor prognosis
Stattic selectively antagonizes STAT3Y705 phosphorylation and inactivates STAT3 in pancreatic cancer cells (PCCs) To further explore the potential anti-tumor mechanisms of Stattic, we evaluated the effects of Stattic on the activities of several signaling pathways that are involved in the occurrence and development of PC
Mutations in the TP53 gene occur in up to 70% of PC cases [30]. p53 acts to inhibit cell proliferation by transcriptionally activating target genes involved in regulating cell cycle, including genes producing cyclins and cyclin-dependent kinases (CDKs) [31]

Summary

Introduction

Pancreatic cancer (PC) is generally associated with poor prognosis. Most PC patients receive chemotherapy as mainstay treatment, but resistance to chemotherapy drugs leads to poor treatment effects [5, 6]. For this reason, new and more effective drugs are necessary. Impaired apoptosis and proliferation of PCCs are regarded as a major cause of poor prognosis in PC [7]. Extensive evidence shows that STAT3 overactivation induces angiogenesis, immunosuppression, and metastasis, and suppresses apoptosis and inflammation, eventually resulting in PC among other cancers [8–10]. As a result, activated STAT3 upregulates proliferation-related factors, leading to excessive proliferation of tumor cells. Enhanced STAT3 activity promotes PCC malignance and is strongly associated with poor prognosis [14–16]. Targeting STAT3 could potentially be utilized as effective anti-PC strategies

Methods

Results

Conclusion