Bioactive Ent-Kaurane Diterpenes Oridonin and Irudonin Prevent Cancer Cells Migration by Interacting with the Actin Cytoskeleton Controller Ezrin

Abstract

The ent-kaurane diterpene oridonin was reported to inhibit cell migration and invasion in several experimental models. However, the process by which this molecule exerts its anti-metastatic action has not been yet elucidated. In this article, we have investigated the anti-metastatic activity of Oridonin and of one homolog, Irudonin, with the aim to shed light on the molecular mechanisms underlying the biological activity of these ent-kaurane diterpenes. Cell-based experiments revealed that both compounds are able to affect differentiation and cytoskeleton organization in mouse differentiating myoblasts, but also to impair migration, invasion and colony formation ability of two different metastatic cell lines. Using a compound-centric proteomic approach, we identified some potential targets of the two bioactive compounds among cytoskeletal proteins. Among them, Ezrin, a protein involved in the actin cytoskeleton organization, was further investigated. Our results confirmed the pivotal role of Ezrin in regulating cell migration and invasion, and indicate this protein as a potential target for new anti-cancer therapeutic approaches. The interesting activity profile, the good selectivity towards cancer cells, and the lower toxicity with respect to Oridonin, all suggest that Irudonin is a very promising anti-metastatic agent.

Oridonin suppresses gastric cancer SGC‐7901 cell proliferation by targeting the TNF‐alpha/androgen receptor/TGF‐beta signalling pathway axis

“…At present, the relevant literature on the antitumor effects of oridonin are focused on the following aspects: inducing apoptosis by arresting the cell cycle, 37 inducing DNA damage, 38,39 inducing autophagy, 15 inhibiting tumour angiogenesis 3 and inhibiting the migration of tumour cells 18,19,40 . It is relatively single‐sided, and lacks comprehensive and multi‐angle research.…”

“…At present, the relevant literature on the antitumor effects of oridonin are focused on the following aspects: inducing apoptosis by arresting the cell cycle, 37 inducing DNA damage, 38 , 39 inducing autophagy, 15 inhibiting tumour angiogenesis 3 and inhibiting the migration of tumour cells. 18 , 19 , 40 It is relatively single‐sided, and lacks comprehensive and multi‐angle research. The network pharmacology has broken the barriers in the study of traditional Chinese medicine, which makes it easier for us to apply the technology of experimental science to study traditional Chinese medicine.…”

Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK

“…Cell viability was established by measuring mitochondrial metabolic activity with PrestoBlueTM (PB) (Cat. N. A13262, Invitrogen), employed according to the manufacturer’s protocol [ 50 ]. In brief, SH-SY5Y (5 × 10 4 cells/well) were plated into 96-well plates for 24 h, then the cocoa raw extract (1–50 µg/mL) or its fractions (1–6 µg/mL) were added for 1 h. Next, 6-OHDA was added for 24 h. Afterward, PB reagent at 10% final concentration for 2 h was added.…”

ER exit pathways and the control of proteostasis: Crucial role of the UPR, COPII, and ER-phagy in the secretory pathway

“…In contrast, UPR does not induce changes in the intracellular pattern of Sec16. Immunofluorescence was conducted on Huh7 cells as previously described (Amodio et al, 2017;Pagliara et al, 2020;Rapa et al, 2021). Briefly, Huh7 cells seeded on glass coverslips were either not treated (CTRL) or treated with 300 nM thapsigargin for 2 h and processed for immunofluorescence with anti-Sec31 (BD Transduction Laboratories) and anti-Sec16 (Bethyl Laboratories) specific antibodies.…”