title: CHK1 affects cell sensitivity to microtubule-targeted drugs.
abstract: Microtubules are the target of many anticancer drugs. Understanding the mechanism by which cells respond to different microtubule-targeted drugs is important to resolve the drug resistance and to gain better tumor control. We report here for the first time that CHK1, an essential protein in mammalian cells, affects cell sensitivity to microtubule-targeted drugs. By using a pair of transformed rat fibroblast cell lines, we show that compared with their counterpart B4 cells, A1-5 cells with higher CHK1 expression are more resistant to taxotere, a microtubule stabilizer, but are more sensitive to nocodazole, a microtubule destabilizer. We also show that the altered sensitivities of A1-5 cells to either taxotere or to nocodazole are related to the lesser microtubule-formation in the cells. In addition, we show that the altered drug sensitivities and less microtubules-formation shown in A1-5 cells could be efficiently reversed by Chk1 siRNA. Taken together, these results indicate that CHK1 is one of the factors affecting cell resistance to taxotere and sensitiveness to nocodazole, suggesting that CHK1 is involved in affecting microtubule dynamics and could be inhibited for taxotere sensitization in CHK1 highly expressed tumor cells.
authors.affiliation: Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ren
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Adam
authors.initials: A
authors.lastname: Dicker
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002461:Cell Line, Transformed; D000071877:Checkpoint Kinase 1; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D015739:Nocodazole / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat; D015739:Nocodazole