Selective Activation of ZAK β Expression by 3-Hydroxy-2-Phenylchromone Inhibits Human Osteosarcoma Cells and Triggers Apoptosis via JNK Activation

Abstract

Although various advancements in radical surgery and neoadjuvant chemotherapy have been developed in treating osteosarcoma (OS), their clinical prognosis remains poor. A synthetic chemical compound, 3-hydroxylflavone, that is reported to regulate ROS production is known to inhibit human bone osteosarcoma cells. However, its role and mechanism in human OS cells remains unclear. In this study, we have determined the potential of 3-Hydroxy-2-phenylchromone (3-HF) against OS using human osteosarcoma (HOS) cells. Our previous studies showed that Zipper sterile-alpha-motif kinase (ZAK), a kinase member of the MAP3K family, was involved in various cellular events such as cell proliferation and cell apoptosis, and encoded two transcriptional variants, ZAKα and β. In this study, we show that 3-HF induces the expression of ZAK and thereby enhances cellular apoptosis. Using gain of function and loss of function studies, we have demonstrated that ZAK activation by 3-HF in OS cells is confined to a ZAKβ form that presumably plays a leading role in triggering ZAKα expression, resulting in an aggravated cancer apoptosis. Our results also validate ZAKβ as the predominant form of ZAK to drive the anticancer mechanism in HOS cells.

Network pharmacology-based investigation and experimental validation of the mechanism of scutellarin in the treatment of acute myeloid leukemia

“…It promotes apoptosis via the transcriptional regulation or phosphorylation of the key mitochondrial pro- and anti-apoptotic proteins ( Dhanasekaran & Reddy, 2008 ). Modulation of the JNK pathway has been recognized as an effective avenue to treat cancers, including oral tumors, osteosarcoma, and colorectal cancer ( Fu et al, 2020 ; Kon-Young Ji 2021 ; Liu et al, 2021 ), especially AML ( Torres et al, 2010 ; Bomfim et al, 2019 ; Tian et al, 2019 ).…”

Principle active metabolites of Pinus morrisonicolaHayata synergistically inhibit cell proliferation and autophagy to elevate apoptosis in hepatocellular carcinoma cells

“…The membranes were rinsed with Tris‐buffered saline with 0.1% Tween® 20 detergent (TBST) and incubated with the secondary antibody for 1 h. Blots were then visualized with enhanced Chemiluminescence solution and for repeated hybridization the PVDF membranes were stripped by incubating in western blot Stripping buffer for 10 min. The intensity of blots were measured with imageJ 1.52v (NIH, Bethesda, MD) 21 software.…”

MAP3K Family Review and Correlations with Patient Survival Outcomes in Various Cancer Types

“…Existing literature identifies MAP3K20 as an ERK and JNK activator with multiple isoforms. Some isoforms of MAP3K20 have been identified to be positively correlated with gastric and colorectal cancer development while others have been demonstrated to have anti-tumor roles by promoting apoptosis in osteosarcoma [146][147][148][149]. The mRNA expression of MAP3K20 was associated with increased survival in esophageal squamous cell carcinoma and sarcoma.…”