Disruption of Microtubules Sensitizes the DNA Damage-induced Apoptosis Through Inhibiting Nuclear Factor kappaB (NF-kappaB) DNA-binding Activity.
10.3346/jkms.2010.25.11.1574
- Author:
Hyunji LEE
1
;
Juhee JEON
;
Young Sue RYU
;
Jae Eun JEONG
;
Sanghee SHIN
;
Tiejun ZHANG
;
Seong Wook KANG
;
Jang Hee HONG
;
Gang Min HUR
Author Information
1. Department of Pharmacology, Research Institute for Medical Science, Daejeon Regional Cancer Center, Daejeon, Korea. gmhur@cnu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
NF-kappa B;
Apoptosis;
DNA Damage;
Microtubules;
Signaling;
DNA Damage
- MeSH:
Animals;
Antibiotics, Antineoplastic/therapeutic use;
*Apoptosis;
Caspases/metabolism;
Cell Line;
Colchicine/pharmacology;
DNA/metabolism;
*DNA Damage;
Doxorubicin/therapeutic use;
Humans;
Mice;
Microtubules/chemistry/*drug effects/metabolism;
NF-kappa B/antagonists & inhibitors/*metabolism;
Neoplasms/drug therapy;
Nocodazole/pharmacology;
Protein Binding;
Signal Transduction;
Tubulin Modulators/*pharmacology;
Vinblastine/pharmacology
- From:Journal of Korean Medical Science
2010;25(11):1574-1581
- CountryRepublic of Korea
- Language:English
-
Abstract:
The massive reorganization of microtubule network involves in transcriptional regulation of several genes by controlling transcriptional factor, nuclear factor-kappa B (NF-kappaB) activity. The exact molecular mechanism by which microtubule rearrangement leads to NF-kappaB activation largely remains to be identified. However microtubule disrupting agents may possibly act in synergy or antagonism against apoptotic cell death in response to conventional chemotherapy targeting DNA damage such as adriamycin or comptothecin in cancer cells. Interestingly pretreatment of microtubule disrupting agents (colchicine, vinblastine and nocodazole) was observed to lead to paradoxical suppression of DNA damage-induced NF-kappaB binding activity, even though these could enhance NF-kappaB signaling in the absence of other stimuli. Moreover this suppressed NF-kappaB binding activity subsequently resulted in synergic apoptotic response, as evident by the combination with Adr and low doses of microtubule disrupting agents was able to potentiate the cytotoxic action through caspase-dependent pathway. Taken together, these results suggested that inhibition of microtubule network chemosensitizes the cancer cells to die by apoptosis through suppressing NF-kappaB DNA binding activity. Therefore, our study provided a possible anti-cancer mechanism of microtubule disrupting agent to overcome resistance against to chemotherapy such as DNA damaging agent.
