title: The microtubule poison vinorelbine kills cells independently of mitotic arrest and targets cells lacking the APC tumour suppressor more effectively.
abstract: Colorectal cancers commonly carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein contributes to the stabilization of microtubules. Consistently, microtubules in cells lacking APC depolymerize more readily in response to microtubule-destabilizing drugs. This raises the possibility that such agents are suitable for treatment of APC-deficient cancers. However, APC-deficient cells have a compromised spindle assembly checkpoint, which renders them less sensitive to killing by microtubule poisons whose toxicity relies on the induction of prolonged mitotic arrest. Here, we describe the novel discovery that the clinically used microtubule-depolymerizing drug vinorelbine (Navelbine) kills APC-deficient cells in culture and in intestinal tissue more effectively than it kills wild-type cells. This is due to the ability of vinorelbine to kill cells in interphase independently of mitotic arrest. Consistent with a role for p53 in cell death in interphase, depletion of p53 renders cells less sensitive to vinorelbine, but only in the presence of wild-type APC. The pro-apoptotic protein BIM (also known as BCL2L11) is recruited to mitochondria in response to vinorelbine, where it can inhibit the anti-apoptotic protein BCL2, suggesting that BIM mediates vinorelbine-induced cell death. This recruitment of BIM is enhanced in cells lacking APC. Consistently, BIM depletion dampens the selective effect of vinorelbine on these cells. Our findings reveal that vinorelbine is a potential therapeutic agent for colorectal cancer, but they also illustrate the importance of the APC tumour suppressor status when predicting therapeutic efficacy.
authors.affiliation: Division of Cell and Developmental Biology, University of Dundee, Dow Street, Dundee, DD1 5EH,  UK.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Klotz
authors.forename: Scott A
authors.initials: SA
authors.lastname: Nelson
authors.forename: Karin
authors.initials: K
authors.lastname: Kroboth
authors.forename: Ian P
authors.initials: IP
authors.lastname: Newton
authors.forename: Sorina
authors.initials: S
authors.lastname: Radulescu
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Paul L
authors.initials: PL
authors.lastname: Appleton
authors.forename: Inke S
authors.initials: IS
authors.lastname: Näthke
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007399:Interphase / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D000077235:Vinorelbine