Nannocystin ax, an eEF1A inhibitor, induces G1 cell cycle arrest and caspase-independent apoptosis through cyclin D1 downregulation in colon cancer in vivo
Membrane Potential, Mitochondrial
0301 basic medicine
0303 health sciences
Down-Regulation
Antineoplastic Agents
Apoptosis
HCT116 Cells
G1 Phase Cell Cycle Checkpoints
3. Good health
03 medical and health sciences
Peptide Elongation Factor 1
Caspases
Depsipeptides
Colonic Neoplasms
Animals
Humans
Cyclin D1
HT29 Cells
Zebrafish
DOI:
10.1016/j.phrs.2021.105870
Publication Date:
2021-09-07T01:18:53Z
AUTHORS (11)
ABSTRACT
Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide. Nannocystin ax (NAN), a 21-membered cyclodepsipeptide initially isolated from myxobacteria of the Nannocystis genus, was found to target the eukaryotic elongation factor 1A (eEF1A). The current study was designed to evaluate the anticancer effect and underlying mechanisms of NAN with in vitro and in vivo models. Results showed that NAN induced G1 phase cell cycle arrest and caspase-independent apoptosis in HCT116 and HT29 human CRC cells. NAN significantly downregulated cyclin D1 level in a short time, but NAN did not affect the transcription level and ubiquitin-dependent degradation of cyclin D1. Furthermore, NAN treatment directly targeted eEF1A and partially decreased the synthesis of new proteins, contributing to the downregulation of cyclin D1. Besides, NAN significantly suppressed tumor growth in the zebrafish xenograft model. In conclusion, NAN triggered G1 phase cell cycle arrest through cyclin D1 downregulation and eEF1A-targeted translation inhibition and promoted caspase-independent apoptosis in CRC cells.
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