TY - JOUR
T1 - Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins
AU - Poruchynsky, Marianne S.
AU - Komlodi-Pasztor, Edina
AU - Trostel, Shana
AU - Wilkerson, Julia
AU - Regairaz, Marie
AU - Pommierb, Yves
AU - Zhang, Xu
AU - Maity, Tapan Kumar
AU - Robey, Robert
AU - Burotto, Mauricio
AU - Sackettc, Dan
AU - Guha, Udayan
AU - Fojo, Antonio Tito
PY - 2015/2/3
Y1 - 2015/2/3
N2 - The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.
AB - The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.
KW - Combination chemotherapy,targeted therapies
KW - DNA-damaging agents
KW - Dna repair protein trafficking
KW - Microtubule targeting agents
UR - http://www.scopus.com/inward/record.url?scp=84922236597&partnerID=8YFLogxK
U2 - 10.1073/pnas.1416418112
DO - 10.1073/pnas.1416418112
M3 - Article
C2 - 25605897
AN - SCOPUS:84922236597
SN - 0027-8424
VL - 112
SP - 1571
EP - 1576
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -