Differentiation-inducing and anti-proliferative activities of isoliquiritigenin and all-trans-retinoic acid on B16F0 melanoma cells: Mechanisms profiling by RNA-seq

Abstract

Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of malignant melanoma has significantly increased over the last decade. With the development of therapy, the survival rate of some kind of cancer has been improved greatly. But the treatment of melanoma remains unsatisfactory. Much of melanoma's resistance to traditional chemotherapy is believed to arise intrinsically, by virtue of potent growth and cell survival-promoting genetic alteration. Therefore, significant attention has recently been focused on differentiation therapy, as well as differentiation inducer compounds. In previous study, we found isoliquiritigenin (ISL), a natural product extracted from licorice, could induce B16F0 melanoma cell differentiation. Here we investigated the transcriptional response of melanoma differentiation process induced by ISL and all-trans-retinoic acid (RA). Results showed that 390 genes involves in 201 biochemical pathways were differentially expressed in ISL treatment and 304 genes in 193 pathways in RA treatment. Differential expressed genes (DGEs, fold-change (FC)≥10) with the function of anti-proliferative and differentiation inducing indicated a loss of grade malignancy characteristic. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated glutathione metabolism, glycolysis/gluconeogenesis and pentose phosphate pathway were the top three relative pathway perturbed by ISL, and mitogen-activated protein kinase (MAPK) signaling pathway was the most important pathway in RA treatment. In the analysis of hierarchical clustering of DEGs, we discovered 72 DEGs involved in the process of drug action. We thought Cited1, Tgm2, Xaf1, Cd59a, Fbxo2, Adh7 may have critical role in the differentiation of melanoma. The evidence displayed herein confirms the critical role of reactive oxygen species (ROS) in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics.

Reprogramming induced by isoliquiritigenin diminishes melanoma cachexia through mTORC2-AKT-GSK3β signaling

“…In our previous studies, we demonstrated that differentiation of mouse melanoma cells induced by ISL was responsible for diminishing cancer cell cachexia [26]. We also found that ISL altered melanin anabolism and glycolysis of mouse melanoma cells in our recent work [27, 28]. In this study, we hypothesized that ISL was capable of inducing human melanoma reprogramming and we investigated the underlying mechanism of action.…”

“…ISL has been shown to have anti-tumor activity in vitro and in vivo [22–24]. Previously, we reported that ISL induced cancer cell differentiation [25, 26], and reduced glycolysis in a mouse melanoma cell line [27, 28]. Despite these advances, very little is known about the pharmacological mechanism of action of ISL in human melanoma cell lines.…”

Mechanisms underlying isoliquiritigenin‐induced apoptosis and cell cycle arrest via ROS‐mediated MAPK/STAT3/NF‐κB pathways in human hepatocellular carcinoma cells

“…In addition, some studies have indicated that ROS are second messengers that activate the MAPK cascade and the NF‐κB transcription factor, and it has been suggested that ROS‐induced apoptosis is mediated via the MAPK and NF‐κB pathways (Akanda et al, ; Liu et al, ; Panahi, Pasalar, Zare, Rizzuto, & Meshkani, ). A recent study indicated that ISL induces apoptosis by inhibiting NF‐κB in chondrocyte‐like ATDC5 cells, and can also exert its antiproliferative effects by regulating ROS levels and MAPK signaling in B16F0 melanoma cells (Chen et al, ; Ji et al, ). In line with these findings, the results of our study revealed that ISL increases the expression levels of p‐JNK, p‐p38, and IκB, while decreasing the levels of p‐ERK, p‐STAT3, NF‐κB (p65) in cytoplasm and STAT3, NF‐κB (p65), and p‐IκB in nucleus (Figure ).…”

Transcriptome Analysis of Canine Cutaneous Melanoma and Melanocytoma Reveals a Modulation of Genes Regulating Extracellular Matrix Metabolism and Cell Cycle

“…The use of RNA sequencing (RNA-seq) technology has expanded the diagnostic, prognostic and therapeutic opportunities in cancer research, allowing the recognition of gene fusions and differential expression of disease-associated transcripts 17, 18 . In the melanoma field, many studies have focused on RNA-seq of melanocytes 19 and melanoma cell lines 20–22 and only very recently few of them on whole tumor samples or single malignant, immune, stromal and endothelial cells 18, 23–26 . In veterinary medicine, this technique has been used in recent years to study degenerative diseases and stress-related conditions and only rarely has it applied to tumor analysis in canine head and neck carcinoma, mammary carcinoma and lymphoma 27–30 .…”