Strictosamide and mitraphylline inhibit cancer cell motility by suppressing epithelial-mesenchymal transition via integrin α4-mediated signaling

Epithelial-mesenchymal transition (EMT) is a critical process in Cancer cell motility and metastasis. Monoterpene Indole Alkaloids (MIAs) have been widely investigated for biological activities, but rarely been explored for cell motility inhibition. This study aimed to discover natural products, especially focusing on MIAs, that inhibit EMT in Cancer cells, based on our screening using multiple plant extracts. We found that an extract of the aerial parts of Uncaria scandens (Sm.) Wall. (Rubiaceae) decreased Cancer cell motility. Targeted isolation exhibited eight MIAs. Among them, strictosamide and mitraphylline suppressed the invasion and migration of the cells. The alteration of the mRNA expression of the EMT effectors and transcription factors suggested that the EMT signaling pathway is related to the suppression of Cancer cell motility by both compounds. RT-PCR gene array suggested inhibition of Integrin α4 signaling as a potential mechanism of the EMT inhibition, which was supported by the quantitative analysis of the mRNA expressions of the related genes. Together, present study is the first report highlighting the cell motility-suppressive effects of strictosamide and mitraphylline. Our results suggested the potential applicability of strictosamide and mitraphylline for the prevention of metastasis.

Bioactivity-guided fractionation; Integrin Α4β1 agonist; Metastasis suppressor; Spirocylic oxindole alkaloid; Vallesiachotaman-type alkaloid.