Abstract
Simple SummarySTAT3 is a major oncogenic transcription factor that is constitutively activated in many types of human cancers, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Many STAT3 inhibitors have gained momentum in clinical trials towards the treatment of various cancers. In the present study, we have investigated the STAT3 inhibitory efficacy of Tris DBA, a palladium-based compound, in HCC and MM cancer cells and preclinical cancer models. Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) abrogated the STAT3 signaling pathway in both models by elevating the expression of SHP2. Functionally, Tris DBA inhibited cell proliferation, migration, invasion, and regressed tumor metastasis. Although many studies propose Tris DBA as a modulator of MAPK, Akt, phospho-S6 kinase, and N-myristoyltransferase-1, we have comprehensively demonstrated for the first time that Tris DBA is an inhibitor of STAT3 signaling in preclinical cancer models. These results support the consideration of Tris DBA in clinical trials in translational relevance.STAT3 is an oncogenic transcription factor that controls the expression of genes associated with oncogenesis and malignant progression. Persistent activation of STAT3 is observed in human malignancies, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA) on STAT3 signaling in HCC and MM cells. Tris DBA decreased cell viability, increased apoptosis, and inhibited IL-6 induced/constitutive activation of STAT3, JAK1, JAK2, and Src in HCC and MM cells. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated the expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation, and the inhibition of SHP2 reversed this effect. Tris DBA downregulated the expression of STAT3-driven genes, suppressed cell migration/invasion. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC preclinical mice models with a reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying significant toxicity. Overall, Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.
Highlights
Cancer is a prominent public health concern and the second major cause of death globally after cardiovascular disease and both its incidence and mortality rates are increasing every year [1,2,3]
We have evaluated the effect of Tris DBA on STAT3 signaling in hepatocellular carcinoma (HCC) and MM cells and its antitumor efficacy in preclinical settings
These results suggest that the induction of Tris DBA-induced apoptosis is mediated at least in part through the mitigation of the STAT3 signaling pathway
Summary
Cancer is a prominent public health concern and the second major cause of death globally after cardiovascular disease and both its incidence and mortality rates are increasing every year [1,2,3]. Hepatocellular carcinoma (HCC) is the leading type of liver cancer, affecting 0.8 million people in 2012 throughout the globe [4], and the five-year survival rate has been estimated to be between 5% and 14%, which is critically low [5]. B infection remains the leading risk factor of HCC followed by non-alcoholic fatty liver disease, alcoholic hepatitis, aflatoxin B1 intake, and hemochromatosis [6,7]. Precise risk factors are not clearly listed, factors such as age, gender, race, and family history are often believed to contribute to the development of MM [13] Multiple myeloma (MM) stands second among hematological malignancies in Western countries, contributing approximately 10% of hematological malignancies [10,11,12].
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