Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma

Abstract

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)–mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phospho-tyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM.

Potential Anticancer Properties and Mechanisms of Action of Withanolides

“…STAT3 inhibiting capacity of WFA has been reported recently (Table 1). By using neuroblastoma and multiple myeloma tumor cells, Yco et al demonstrated that WFA induced dosedependent cell death and blocked the transcriptional activity of STAT3 by inhibition of SAT3 phosphorylation (Tyr705) [11]. In silico molecular docking analysis revealed the possibility of intermolecular interaction between WFA with STAT3 in the SH2 domain.…”

“…SH2 domain typically functions as a phosphorylated tyrosine recognition domain on other proteins hence playing crucial role in signal transduction. It is postulated that binding of WFA can directly block dimer formation via changes in physical-chemical factors, such as charge, hydrogen binding, solvent accessibility, and side-chain conformations [11]. WFA also inhibits growth of human breast cancer cells by inhibiting constitutive as well as IL-6-inducible phosphorylation of STAT3 (Tyr 705) [97].…”

“…Neuroblastoma and multiple myeloma [11] Breast cancer [97] Renal cancer cells [98] ROS Head and neck cancer [24] Glioblastoma [99] RSK/DR5 Breast cancer [16] NF-κB inhibition Leukemia cell line (U937); inducer TNF [12] Multiple myeloma U266 cells [100] Breast cancer [101] Colon carcinoma [18] Myeloid leukemia [102] T-cell lymphoma [47] Cervical cancer [103] Notch1…”

“…WFA has shown to have potent cytotoxic effects on various cancer cell types. Anticancer activity of WFA has been reported against uveal melanoma [9], glioblastoma cells [10], neuroblastoma and multiple myeloma [11], leukemia [12,13], breast [14][15][16][17], colon [18], ovarian [19], pancreatic [20], prostate [21,22], thyroid [23], and head and neck cancer cells [24].…”

Combination of PEI-Mn0.5Zn0.5Fe2O4 nanoparticles and pHsp 70-HSV-TK/GCV with magnet-induced heating for treatment of hepatoma

“…38,39 Studies have suggested that the persistent activation of Stat3 plays a key role in resistance to apoptosis of signal transduction pathways in hepatocellular carcinoma. 40 combination of PeI-MZF-NPs and hsV-TK/gcV for treatment of hepatoma…”