Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E.

Abstract

Cucurbitacin E (CuE) or α-elaterin is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigated the anticancer effects of CuE on colorectal cancer (CRC) using primary cell lines isolated from five CRC patients in Taiwan, Specifically, we explored the anti-proliferation and cell cycle G2/M arrest induced by CuE in CRC cells. MPM-2 flow cytometry tests show that CuE-treated cells accumulated in metaphase (CuE 2.5-7.5 μM). Results further indicate that CuE produced G2/M arrest as well as the downregulation of CDC2 and cyclin B1 expression and dissociation. Both effects increased proportionally with the dose of CuE; however, the inhibition of proliferation, arrest of mitosis, production of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (ΔΨm) were found to be dependent on the quantity of CuE used to treat the cancer cells. In addition, cell cycle arrest in treated cells coincided with the activation of the gene GADD45(α, β, γ). Incubation with CuE resulted in the binding of GADD45γ to CDC2, which suggests that the delay in CuE-induced mitosis is regulated by the overexpression of GADD45γ. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activities in established CRC.

• Authors: Y-C Hsu, T-Y Huang, M-J Chen
• Journal: Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1198 (Apr 24 2014) ISSN: 2041-4889 [Electronic] England
• PMID: 24763055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin B1
• GADD45 protein
• Intracellular Signaling Peptides and Proteins
• Reactive Oxygen Species
• Triterpenes
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• cucurbitacin E

Topics

• Apoptosis (drug effects)
• CDC2 Protein Kinase
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (genetics, pathology)
• Cyclin B1 (metabolism)
• Cyclin-Dependent Kinases (metabolism)
• Down-Regulation (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mitosis (drug effects)
• Mitotic Index
• Necrosis
• Reactive Oxygen Species (metabolism)
• Triterpenes (pharmacology)
• Up-Regulation (drug effects)