Apicularen A induces cell death through Fas ligand up-regulation and microtubule disruption by tubulin down-regulation in HM7 human colon cancer cells
SCIE
SCOPUS
- Title
- Apicularen A induces cell death through Fas ligand up-regulation and microtubule disruption by tubulin down-regulation in HM7 human colon cancer cells
- Authors
- YUN, EUN JIN; Kim, Jong-Seok; Lee, Young-Chul; Nam, Ho-Tak; Li, Ge; Song, Kyoungsub; Seo, Kang-Sik; Park, Ji-Hoon; Ahn, Jong-Woong; Zee, Okpyo; Park, Jong-Il; Yoon, Wan-Hee; Lim, Kyu; Hwang, Byung-Doo
- Date Issued
- 2007-11-01
- Publisher
- AMER ASSOC CANCER RESEARCH
- Abstract
- Purpose: Apicularen A has been shown to cause growth inhibition and apoptosis in several cancer cell lines. However, the mechanisms of apicularen A-induced cell death and in vivo effects remain unclear. In this study, we investigated the molecular mechanisms of apicularen A-induced cell death in HM7 human colon cancer cells in vitro and anticancer activity in vivo.
Experimental Design: We tested cytotoxicity with a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, apoptosis with DNA fragmentation assay, mitochondrial membrane potential, and cell cycle with fluorescence-activated cell sorting. Caspase activation was done by fluorometry. Alterations of microtubule structure, tubulin protein, and mRNA level were assessed by immunofluorescence, Western blot, and reverse transcription- PCR. In vivo studies were assessed using nude mice tumor cell growth in xenograft model and liver colonization assay.
Results: Apicularen A treatment of HM7 cells inhibited cell growth and this inhibition was partially rescued by z-VAD-fmk. Apicularen A caused accumulation of sub-G(1)-G(0), DNA fragmentation, Fas ligand induction, and activation of caspase-8 and caspase-3, but mitochondrial membrane potential was not changed. Furthermore, beta-tubulin protein and mRNAwere decreased by apicularen A, but in vitro polymerization of tubulin was not affected. Concurrently, apicularen A -treated cell showed disruption of microtubule architecture. In in vivo studies, apicularen A reduced tumor volume by similar to 72% at the end of a 15-day treatment. Moreover, apicularen A reduced liver colonization as much as 95.6% (50 mu g/kg/d).
Conclusion: Apicularen A induces cell death of HM7 cells through up-regulating Fas ligand and disruption of microtubule architecture with down-regulation of tubulin level. These findings indicate that apicularen A is a promising new microtubule-targeting compound.
- Keywords
- INDUCED APOPTOSIS; RAW-264.7 CELLS; CARCINOMA-CELLS; IN-VITRO; ACTIVATION; INDUCTION; GROWTH; LINE; METASTASIS; CASPASE
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/40848
- DOI
- 10.1158/1078-0432.CCR-07-1428
- ISSN
- 1078-0432
- Article Type
- Article
- Citation
- CLINICAL CANCER RESEARCH, vol. 13, no. 21, page. 6509 - 6517, 2007-11-01
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