Polygonum cuspidatum Extract (Pc-Ex) Containing Emodin Suppresses Lung Cancer-Induced Cachexia by Suppressing TCF4/TWIST1 Complex-Induced PTHrP Expression

Abstract

Cachexia, which is characterised by the wasting of fat and skeletal muscles, is the most common risk factor for increased mortality rates among patients with advanced lung cancer. PTHLH (parathyroid hormone-like hormone) is reported to be involved in the pathogenesis of cancer cachexia. However, the molecular mechanisms underlying the regulation of PTHLH expression and the inhibitors of PTHLH have not yet been identified. The PTHLH mRNA levels were measured using quantitative real-time polymerase chain reaction, while the PTHrP (parathyroid hormone-related protein) expression levels were measured using Western blotting and enzyme-linked immunosorbent assay. The interaction between TCF4 (Transcription Factor 4) and TWIST1 and the binding of the TCF4–TWIST1 complex to the PTHLH promoter were analysed using co-immunoprecipitation and chromatin immunoprecipitation. The results of the mammalian two-hybrid luciferase assay revealed that emodin inhibited TCF4–TWIST1 interaction. The effects of Polygonum cuspidatum extract (Pc-Ex), which contains emodin, on cachexia were investigated in vivo using A549 tumour-bearing mice. Ectopic expression of TCF4 upregulated PTHLH expression. Conversely, TCF4 knockdown downregulated PTHLH expression in lung cancer cells. The expression of PTHLH was upregulated in cells ectopically co-expressing TCF4 and TWIST1 when compared with that in cells expressing TCF4 or TWIST1 alone. Emodin inhibited the interaction between TCF4 and TWIST1 and consequently suppressed the TCF4/TWIST1 complex-induced upregulated mRNA and protein levels of PTHLH and PTHrP. Meanwhile, emodin-containing Pc-Ex significantly alleviated skeletal muscle atrophy and downregulated fat browning-related genes in A549 tumour-bearing mice. Emodin-containing Pc-Ex exerted therapeutic effects on lung cancer-associated cachexia by inhibiting TCF4/TWIST1 complex-induced PTHrP expression.

Advances for pharmacological activities of Polygonum cuspidatum - A review

“…In vivo and in vitro mechanism research showed that emodin in this PC extract could inhibited transcription factor 4 (TCF4)–TWIST1 (a bHLH-domain-containing transcription factor) interaction, then suppress parathyroid hormone-related protein (PTHrP) expression (Fang et al. 2022 ).…”

Twist1 as a target for prevention of cutaneous squamous cell carcinoma

“…In addition, suppression of the Wnt/β‐catenin pathway has been shown to inhibit human cSCC development 158 . More recent findings suggest that emodin may also hinder Twist1 complexing with transcription factor 4 (TCF4) in lung cancer cells 159 . TCF4 has been shown to be associated with cSCC development independent of Wnt/β‐catenin signaling and thus presents another potential mechanism by which emodin may be used to target Twist1 in the context of cSCC prevention 160 .…”

“…158 More recent findings suggest that emodin may also hinder Twist1 complexing with transcription factor 4 (TCF4) in lung cancer cells. 159 invasion, wound healing, and anchorage-independent growth in several liver cancer cell lines. 163 ADQ was shown to reduce Twist1…”

A Strategy for Pinpointing Natural Bioactive Components Using Two-Dimensional Bioassay Profilings Combined with Comprehensive Two-Dimensional Countercurrent Chromatography × High-Performance Liquid Chromatography

“…It was used for the treatment of hyperlipemia, 21 inflammation, 22 favus, and cancer. 23 Previously, anthraquinones and stilbenes of P. cuspidatum extracts were examined for antityrosinase potency 24 and antiglucosidase potency 25 and also possessed antioxidative properties on radical-scavenging abilities. 26 Meanwhile, bioassay-guided profiling was applied in screening potent natural α-glucosidase and PTP1B inhibitors based on 1D liquid chromatographic separation.…”

“…et Zucc, which was a popular traditional Chinese medicinal herb with a wide spectrum of pharmacological effects. It was used for the treatment of hyperlipemia, inflammation, favus, and cancer . Previously, anthraquinones and stilbenes of P.…”