Disruption of microtubules sensitizes the DNA damage-induced apoptosis through inhibiting nuclear factor κB (NF-κB) DNA-binding activity.
The massive reorganization of microtubule network involves in transcriptional regulation of several genes by controlling transcriptional factor, nuclear factor-kappa B (NF-κB) activity. The exact molecular mechanism by which microtubule rearrangement leads to NF-κB 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-κB binding activity, even though these could enhance NF-κB signaling in the absence of other stimuli. Moreover this suppressed NF-κB 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-κB 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.
Department of Pharmacology, Research Institute for Medical Science, Daejeon Regional Cancer Center, Daejeon, Korea.
Hyunji
H
Lee
Juhee
J
Jeon
Young Sue
YS
Ryu
Jae Eun
JE
Jeong
Sanghee
S
Shin
Tiejun
T
Zhang
Seong Wook
SW
Kang
Jang Hee
JH
Hong
Gang Min
GM
Hur
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy; D015739:Nocodazole / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction; D050257:Tubulin Modulators / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D050257:Tubulin Modulators; D014747:Vinblastine; D004317:Doxorubicin; D004247:DNA; D020169:Caspases; D015739:Nocodazole; D003078:Colchicine