Defining the role of APC in the mitotic spindle checkpoint in vivo: APC-deficient cells are resistant to Taxol.
Mutations in the adenomatous polyposis coli (APC) tumour suppressor are the key initiating event of colorectal cancer. Although the control of WNT signalling is well established as a central tumour-suppressive function, the significance of APC in regulating chromosome instability is less well established. In this study, we test whether APC-deficient cells have a functional spindle assembly checkpoint (SAC) in vivo by examining the response of these cells to Taxol and Vinorelbine. We also show for the first time that APC deficiency compromises the arrest response to Taxol in vivo. This effect is independent of the role that APC has in WNT signalling. At higher levels of Taxol, APC-deficient cells arrest as efficiently as wild-type cells. Importantly, this dose of Taxol strongly suppresses intestinal tumourigenesis in models of benign (APC(Min/+) mouse) and invasive (AhCreER(+)APC(fl/+)PTEN(fl/fl)) cancer. In contrast to intestinal enterocytes with a general SAC defect because of Bub1 (budding uninhibited by benzimidazole 1) deletion, APC-deficient enterocytes arrest equivalently to wild type when treated with Vinorelbine. This suggests that the failed arrest in response to Taxol is because of a specific defect in microtubule stabilization following Taxol treatment rather than a general role of the APC protein in the mitotic spindle checkpoint. In summary, this study clarifies the role of APC as a mitotic spindle checkpoint protein in vivo and shows that APC-deficient cells have a compromised response to Taxol.
Radulescu
S
S
CR-UK Beatson Institute of Cancer Research, Glasgow, UK.
Ridgway
R A
RA
Appleton
P
P
Kroboth
K
K
Patel
S
S
Woodgett
J
J
Taylor
S
S
Nathke
I S
IS
Sansom
O J
OJ
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020895:Enterocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017384:Sequence Deletion; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine; D051153:Wnt Proteins / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D000972:Antineoplastic Agents, Phytogenic; D051153:Wnt Proteins; D014747:Vinblastine; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel; D000077235:Vinorelbine