The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-κB/mTOR prosurvival signaling
| Autor: | Jiajiu Shaw, Subhash C. Gautam, Yiguan Zhang, Xiaohua Gao, Dorrah Deeb, Yongbo Liu, Frederic K A Valeriote |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Cell cycle checkpoint Cell Survival Apoptosis Cell Cycle Proteins Biology 03 medical and health sciences 0302 clinical medicine Cyclin-dependent kinase Cell Line Tumor Survivin Humans Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Cell growth TOR Serine-Threonine Kinases NF-kappa B Cell cycle Cell biology Gene Expression Regulation Neoplastic Pancreatic Neoplasms 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Signal transduction Trichothecenes Proto-Oncogene Proteins c-akt Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | International Journal of Oncology. 49:1139-1147 |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2016.3587 |
| Popis: | Pancreatic ductal adenocarcinoma (PDA) remains one of the most difficult to treat of all malignancies. Multimodality regimens provide only short-term symptomatic improvement with minor impact on survival, underscoring the urgent need for novel therapeutics and treatment strategies for PDA. Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibited cell proliferation and induced apoptosis in breast cancer cells. However, the antitumor activity of VC-A for PDA cells has not been investigated. Here we show potent antitumor activity and the mechanism of action of VC-A in PDA cell lines. VC-A strongly inhibited the proliferation and arrested cells in the S phase of the cell cycle. The blocking of cell cycle progression by VC-A was associated with the inhibition of cell cycle regulatory proteins cyclin D1, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4 and cdk inhibitor WAF1/21. VC-A induced apoptosis in PDA cells as indicated by the increased Annexin V FITC-binding, cleavage of poly(ADP-ribose) polymerase‑1 (PARP-1) and procaspases-3, -8 and -9. VC-A also induced mitochondrial depolarization and release of cytochrome c and it inhibited Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax and Bad). In addition, VC-A reduced the levels of inhibitors of apoptosis survivin and c-IAP-2. Finally, VC-A downregulated the expression of prosurvival phospho-Akt (p-Akt), nuclear factor κB (NF-κB) (p65) and mammalian target of rapamycin (p-mTOR) signaling proteins and their downstream mediators. Together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A for PDA cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-κB/mTOR signaling. |
| Databáze: | OpenAIRE |
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