Suppression of Esophageal Cancer Stem-like Cells by SNX-2112 Is Enhanced by STAT3 Silencing

Abstract

Many studies have demonstrated that cancer stem cells (CSCs) or tumor-initiating cells (TICs) are responsible for tumor cell proliferation, chemotherapy resistance, metastasis, and relapse in various cancers. We, and others, have previously shown that the signal transducer and activator of transcription 3 (STAT3) signaling pathway is responsible for CSCs and TICs growth. Recent reports have indicated that the heat shock protein 90 (Hsp90) is also essential for the survival of CSCs and TICs. SNX-2112 is an Hsp90 inhibitor. However, it remains unclear whether proliferation of esophageal cancer stem-like cells (ECSLCs) is suppressed by SNX-2112 with knockdown of STAT3 (shSTAT3). Here, we explored the association between SNX-2112 with shSTAT3 and the suppression of ECSLCs growth. We found that the expression level of both STAT3 and p-STAT3 was higher in clinical esophageal cancer tissue than in the adjacent normal tissue, using western blot and qPCR analysis. Furthermore, differential expression analysis demonstrated that STAT3 was overexpressed in clinical specimens. We demonstrated that SNX-2112 inhibited cancer cell proliferation, decreased ABCB1 and ABCG2 gene expression levels and reduced the colony formation capacity of ECSLCs, which was enhanced by STAT3 silencing. Flow cytometry analysis revealed that the combination of SNX-2112 and shSTAT3 significantly induced apoptosis and cell cycle arrest at G2/M phase in ECSLCs. Levels of proliferation pathway proteins, including p38, c-Jun N-terminal kinase (JNK), and extracellular signal–regulated kinase (ERK) which were also client proteins of Hsp90, were also reduced. In addition, SNX-2112 with shSTAT3 inhibited the proliferation of ECSLCs in vivo. Finally, STAT3 overexpression eliminated the apoptotic and antiproliferative effects of SNX-2112 on ECSLCs. Hence, these results provide a rationale for the therapeutic potential of the combination of SNX-2112 with shSTAT3 in esophageal cancer, and may indicate new targets for clinical intervention in human cancer.

Combinatorial Strategies to Target Molecular and Signaling Pathways to Disarm Cancer Stem Cells

“…Here the dual treatment strongly inhibits the proliferation of ECSLCs, induces G2/M phase arrest and apoptosis of ECSLCs, significantly decreases the colony formation ability and the colony size of ECSLCs compared with shSTAT3 and SNX-2112 alone ( 132 ). On a molecular point of view, the combined treatment reduces the levels of phosphorylation of Hsp90 client proteins involved in cell proliferation including p-p38, p-JNK and p-ERK, decreases the mRNA level of adenosine triphosphate-binding cassette transporter super-family ABCB1 and ABCG2 and the expression level of pro-survival Bcl-2 protein, and increases the expression level of the pro-apoptotic Bax protein compared with SNX-2112 and shSTAT3 alone groups ( 132 ). In addition, the combined treatment significantly reduces the tumor growth in in vivo ECSLCs xenograft tumor models compared to single treatments ( 132 ).…”

Acacetin restrains the malignancy of esophageal squamous carcinoma cells via regulating JAK2/STAT3 pathway

“…This pathway play vital roles in multiple processes of human tumor, including proliferation, inflammation, and survival (Jin, 2020). As reported, the JAK2/ STAT3 pathway plays a regulatory role in the growth, metastasis of esophageal cancer cells (Liu et al, 2015;Xu et al, 2020). For example, phlorizin from sweet tea inhibits the growth, migration, aggressiveness, autophagy, and induces the apoptosis of esophageal cancer cells by antagonizing JAK2/STAT3 signaling pathway (Jia et al, 2021).…”

A Network Pharmacological Elucidation of the Systematic Treatment Activities and Mechanisms of the Herbal Drug FDY003 Against Esophageal Cancer

“…69,70 The JAK-STAT pathway participates in the regulation of angiogenesis, inflammation, colony formation, stemness, invasion, motility, metastasis, EMT, cell cycle progression, growth, anoikis resistance, proliferation, migration, malignant formation, and sensitivity to chemotherapy and radiotherapy in EC cells and tumors. 71–78 It has also been reported that patient survival, TNM stage, lymphatic metastasis, and degree of infiltration in patients with EC are associated with the expression, genetic, and activation statuses of this pathway. 71–78 The NF-kappa B pathway has prognostic value in EC; it represses angiogenesis, metastasis, growth, inflammation, treatment resistance, carcinogenesis, tumorigenesis, and survival of EC cells and tumors.…”

“…71–78 It has also been reported that patient survival, TNM stage, lymphatic metastasis, and degree of infiltration in patients with EC are associated with the expression, genetic, and activation statuses of this pathway. 71–78 The NF-kappa B pathway has prognostic value in EC; it represses angiogenesis, metastasis, growth, inflammation, treatment resistance, carcinogenesis, tumorigenesis, and survival of EC cells and tumors. 79 The programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) checkpoint pathway may be important for the prediction of disease-free survival, overall survival, cancer relapse, treatment response rate and susceptibility, metastasis, lymph node invasion, tumor stage, and incidence of post-therapeutic adverse effects in patients with EC.…”