Journal Article

Dicerandrol C Suppresses Proliferation and Induces Apoptosis of HepG2 and Hela Cancer Cells by Inhibiting Wnt/β-Catenin Signaling Pathway

Zhou, Dongdong, Wu, Jingwan, Liu, Pinghuai, Xu, Jing, Chen, Dandan, Feng, Ting

2024

Overview

Overwhelming evidence points to an aberrant Wnt/β-catenin signaling as a critical factor in hepatocellular carcinoma (HCC) and cervical cancer (CC) pathogenesis. Dicerandrol C (DD-9), a dimeric tetrahydroxanthenone isolated from the endophytic fungus Phomopsis asparagi DHS-48 obtained from mangrove plant Rhizophora mangle via chemical epigenetic manipulation of the culture, has demonstrated effective anti-tumor properties, with an obscure action mechanism. The objective of the current study was to explore the efficacy of DD-9 on HepG2 and HeLa cancer cells and its functional mechanism amid the Wnt/β catenin signaling cascade. Isolation of DD-9 was carried out using various column chromatographic methods, and its structure was elucidated with 1D NMR. The cytotoxicity of DD-9 on HepG2 and HeLa cells was observed with respect to the proliferation, clonality, migration, invasion, apoptosis, cell cycle, and Wnt/β-catenin signaling cascade. We found that DD-9 treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in HepG2 and HeLa cells. The subsequent experiments in vitro implied that DD-63 could significantly suppress the tumor clonality, metastases, and induced apoptosis, and that it arrested the cell cycle at the G0/G1 phase of HepG2 and HeLa cells. Dual luciferase assay, Western blot, and immunofluorescence assay showed that DD-9 could dose-dependently attenuate the Wnt/β-catenin signaling by inhibiting β-catenin transcriptional activity and abrogating β-catenin translocated to the nucleus; down-regulating the transcription level of β-catenin-stimulated Wnt target gene and the expression of related proteins including p-GSK3-β, β-catenin, LEF1, Axin1, c-Myc, and CyclinD1; and up-regulating GSK3-β expression, which indicates that DD-9 stabilized the β-catenin degradation complex, thereby inducing β-catenin degradation and inactivation of the Wnt/β-catenin pathway. The possible interaction between DD-9 and β-catenin and GSK3-β protein was further confirmed by molecular docking studies. Collectively, DD-9 may suppress proliferation and induce apoptosis of liver and cervical cancer cells, possibly at least in part via GSK3-β-mediated crosstalk with the Wnt/β-catenin signaling axis, providing insights into the mechanism for the potency of DD-9 on hepatocellular and cervical cancer.

• Publisher: MDPI AG,MDPI
• Subject: Antimitotic agents / Antineoplastic agents / Antineoplastic Agents - chemistry / Antineoplastic Agents - isolation & purification / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Aquatic plants / beta Catenin - metabolism / Biological products / c-Myc protein / Cancer / Cancer therapies / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - pathology / Cell culture / Cell cycle / Cell migration / Cell Movement - drug effects / Cell proliferation / Cell Proliferation - drug effects / Cells / Cervical cancer / Cervical carcinoma / Chemical properties / Chemotherapy / Chromatography / Columnar structure / Cytotoxicity / Degradation / Diaporthe / dicerandrol C / Drug dosages / Drug therapy / Endophytes / Epigenetics / fluorescent antibody technique / Fungi / G1 phase / Gene expression / genes / Health aspects / HeLa Cells / Hep G2 Cells / Hepatocellular carcinoma / Hepatocytes / Hepatoma / Humans / Identification and classification / Immunofluorescence / Inactivation / Kinases / liver / Liver cancer / Liver Neoplasms - drug therapy / luciferase / mangrove endophytic fungus / Mangroves / Metastases / Metastasis / Molecular docking / Myc protein / neoplasm cells / Neoplasms / NMR / Nuclear magnetic resonance / Organic compounds / Pathogenesis / Pharmaceutical research / Phomopsis asparagi / Phosphorylation / Physiology / Proliferation / Proteins / Rhizophora mangle / Signal transduction / Toxicity / transcription (genetics) / Tumors / uterine cervical neoplasms / Uterine Cervical Neoplasms - drug therapy / Uterine Cervical Neoplasms - pathology / Western blotting / Wnt protein / Wnt Signaling Pathway - drug effects / Wnt/β-catenin signaling / Xanthones - chemistry / Xanthones - isolation & purification / Xanthones - pharmacology / β-Catenin