title: Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: implication in multinucleation and chemosensitization.
abstract: The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, and eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Seon Rang
authors.initials: SR
authors.lastname: Woo
authors.forename: Chang-Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: Kyoung-Mi
authors.initials: KM
authors.lastname: Juhn
authors.forename: Yeun-Jin
authors.initials: YJ
authors.lastname: Ju
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Shin
authors.forename: Hyun-Yoo
authors.initials: HY
authors.lastname: Joo
authors.forename: Eun Ran
authors.initials: ER
authors.lastname: Park
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Jung-Kee
authors.initials: JK
authors.lastname: Lee
authors.forename: Hae Kwon
authors.initials: HK
authors.lastname: Kim
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Gil Hong
authors.initials: GH
authors.lastname: Park
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D043171:Chromosomal Instability; D033481:Chromosomes, Mammalian / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050257:Tubulin Modulators; D017239:Paclitaxel