Dihydromyricetin induced lncRNA MALAT1-TFEB-dependent autophagic cell death in cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. Dihydromyricetin (DHM), a Rattan tea extract, has been shown to have antitumor activity with no obvious toxicity to normal cells in vitro and in vivo. However, its efficacy in the treatment of CSCC and the underlying antitumor mechanism has not been fully elucidated yet. In our study, DHM increased autophagic flux in the A431 cells, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blocking autophagy decreased DHM-induced cell death, indicating DHM triggered autophagic cell death in A431 cells. Specifically, DHM induced TFEB (Ser142) de-phosphorylation, activated TFEB nuclear translocation and increased of TFEB reporter activity, which contributed to the expression of autophagy-related genes and subsequent initiated autophagic cell death in A431 cells. Importantly, DHM decreased lncRNA MALAT1 expression and MALAT1 overexpression abrogated the effects of DHM on TFEB-dependent autophagy both in vitro and in vivo. Taken together, DHM induces CSCC cell death via inducing excessive autophagy, which is mediated through the MALAT1-TFEB pathway. Therefore, DHM may be beneficial for the development of chemotherapy for CSCC.

Dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis via regulating miR-21 in Human Cholangiocarcinoma Cells

“…Dihydromyricetin, the main natural product isolated from the plant Ampelopsis grossedentata, has been widely investigated and shows a variety of biological functions, including ameliorating nonalcoholic fatty liver disease 14 , anti-diabetes 15 and anti-atherosclerosis 10 . In recent years, accumulating in vitro and in vivo studies have been conducted to explore its broad anti-tumor effects 5 , 6 . One study has shown that dihydromyricetin could inhibit cell growth and induce cell apoptosis in the hepatocarcinoma cells, and the underlying mechanism was through inhibiting the Akt/Bad signaling pathway and activating the mitochondrial apoptotic pathway 16 .…”

“…Dihydromyricetin, the most abundant natural flavonoid and active compound in Ampelopsis grossedentata W.T. Wang (Vitaceae) used as herbal tea and traditional Chinese medicines for over hundreds of years in China, has been reported to show potent anti-tumor effects in vitro and in vivo studies [5,6]. For instance, dihydromyricetin combined with irinotecan chemotherapy remarkably delays the progression of colon cancer in mouse models [5].…”

The Roles of ceRNAs-Mediated Autophagy in Cancer Chemoresistance and Metastasis

“…The lncRNA MALAT1 can inhibit autophagy by decoying miR-15b-5p to regulate MAPK1 expression, thereby activating the MAPK1/mTOR signaling [ 87 ]. Consistently, MALAT1 abrogated excessive autophagy in cutaneous squamous cell carcinoma [ 88 ].…”

Molecular Level Insight Into the Benefit of Myricetin and Dihydromyricetin Uptake in Patients With Alzheimer’s Diseases

“…The regulation of autophagy by DMY is a comprehensive and complicated process, which involves the upstream pathway of mTOR including ERK1/2 (extracellular signal-regulated kinase 1/2), AMPK-PGC-1α-Sirt3 (AMP-activated kinase-peroxisome proliferator-activated receptor coactivator-1α-Sirt3) and PI3K/PDK 1/Akt (class III phosphatidylinositol 3-kinase/phosphoinositide-dependent protein kinase 1/protein kinase B) pathways (Xia et al, 2014;Shi et al, 2015). Furthermore, the regulation of autophagy by DMY also involves the Keap-1/Nrf2, ROS-NF-κB, and MALAT1-TFEB pathways (Qiu et al, 2017;Zhou et al, 2017;Tan et al, 2019). In short, DMY can affect the levels of Aβ and tau peptide in the nervous system through multiple effects on autophagy, and thus has a therapeutic effect on AD.…”