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

• Published in: Nutrients Vol. 14; no. 7; p. 1508
• Main Authors: Fang, Xue-Quan, Kim, Young-Seon, Lee, Yoon-Mi, Lee, Mingyu, Lim, Woo-Jin, Yim, Woo-Jong, Han, Min-Woo, Lim, Ji-Hong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05-04-2022; MDPI
• Subjects: Adenoviruses; Animals; Antibodies; Aquatic plants; Atrophy; Biomarkers; Body fat; Breast cancer; Cachexia; Cachexia - drug therapy; Cachexia - etiology; Cachexia - prevention & control; Cell culture; Chromatin; Cytokines; Ectopic expression; Emodin; Emodin - pharmacology; Emodin - therapeutic use; Enzyme-linked immunosorbent assay; Enzymes; Fallopia japonica; Gene expression; Humans; Immunoprecipitation; In vivo methods and tests; Lung cancer; Lung Neoplasms - complications; Lung Neoplasms - drug therapy; Mammals - genetics; Mammals - metabolism; Metabolism; Metastasis; Mice; Molecular modelling; Muscles; Musculoskeletal system; Nuclear Proteins - genetics; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - genetics; Pathogenesis; Plant Extracts; Polygonum cuspidatum; Polymerase chain reaction; Protein expression; Protein synthesis; Proteins; PTHrP; Risk analysis; Risk factors; RNA, Messenger - metabolism; Skeletal muscle; TCF4; Transcription Factor 4 - genetics; Transcription factors; Tumor necrosis factor-TNF; Tumors; Twist-Related Protein 1 - genetics; TWIST1; Western blotting; St Louis Missouri; United States > US; lung cancer; TWIST1; TCF4; PTHrP; cachexia; emodin
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu14071508

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.
(parathyroid hormone-like hormone) is reported to be involved in the pathogenesis of cancer cachexia. However, the molecular mechanisms underlying the regulation of
expression and the inhibitors of PTHLH have not yet been identified. The
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
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
extract (Pc-Ex), which contains emodin, on cachexia were investigated in vivo using A549 tumour-bearing mice. Ectopic expression of TCF4 upregulated
expression. Conversely,
knockdown downregulated
expression in lung cancer cells. The expression of
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.