Cleistanthin A induces apoptosis and suppresses motility of colorectal cancer cells

• Published in: European journal of pharmacology 2020-12, Vol.889, p.173604, Article 173604
• Main Authors: Jearawuttanakul, Kedchin, Khumkhrong, Phattharachanok, Suksen, Kanoknetr, Reabroi, Somrudee, Munyoo, Bamroong, Tuchinda, Patoomratana, Borwornpinyo, Suparerk, Boonmuen, Nittaya, Chairoungdua, Arthit
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Cell Movement - drug effects; Cell Movement - physiology; Cleistanthin A; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Glycosides - pharmacology; Glycosides - therapeutic use; HCT116 Cells; HEK293 Cells; Humans; Invasion; Lignans - pharmacology; Lignans - therapeutic use; Migration; Neoplasm Invasiveness - pathology; Toxins, Biological - pharmacology; Toxins, Biological - therapeutic use; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - physiology; Wnt/β-catenin signaling
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173604

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Here, we investigated the molecular mechanisms that underpin the anticancer effects of cleistanthin A (CA) in two CRC cell lines, HCT 116, and SW480. At 48 h, CA exhibited apoptotic cytotoxic effects in both CRC cell lines, concomitant with reduction of an anti-apoptotic protein, survivin. Mechanistically, CA treatment significantly reduced the expression levels of β-catenin and active-β-catenin in a dose-dependent manner in both CRC cell lines. Moreover, CA suppressed the Wnt/β-catenin signaling pathway by decreasing β-catenin-mediated transcriptional activity and expression of β-catenin target genes, AXIN2, CCND1, and survivin. Furthermore, CA also inhibited transcriptional activity in cells overexpressing a constitutively active β-catenin S33Y, indicating a GSK-3β-independent mechanism underlying the observed CA effects on CRC cells. Although cytotoxic activity was not observed with CA treatment at 24 h, cell migration and invasion were significantly reduced. In addition, CA suppressed V-type ATPase activity and focal adhesion kinase (FAK) phosphorylation. Collectively, our study reveals that CA has time-dependent effects on CRC cell phenotypes. First, short-term CA treatment inhibited CRC cell migration and invasion partly through the suppression of V-type ATPase activity. This suppression resulted in reduced FAK activation. Second, longer-term CA treatment decreased cell viability which correlated with the suppression of Wnt/β-catenin signaling induced transcriptional activity. Altogether, our data suggest that CA has the potential to develop as an effective and novel therapeutic drug for CRC patients. [Display omitted] •CA exhibited apoptotic cytotoxic effects in CRC cell lines.•CA mediated GSK-3β-independent decreasing transcriptional activity of β-catenin.•CA reduced CRC cell migration and invasion.•CA suppressed V-type ATPase activity and FAK phosphorylation.