ASK1-P38 Pathway is Important for Anoikis Induced by Microtubule-Targeting Aryl Chloroethylureas

Authors

  • Jessica S Fortin University of Arizona
  • Alexandre Patenaude BC Cancer Research Centre
  • Rena G Deschesnes
  • Marie-France Côté Unité de Biotechnologie et de Bioingénierie
  • Eric Petitclerc Unité de Biotechnologie et de Bioingénierie
  • René C.-Gaudreault Unité de Biotechnologie et de Bioingénierie

DOI:

https://doi.org/10.18433/J31G6C

Abstract

PURPOSE. We investigated the involvement of MAPK signaling in the cell death mechanisms of classical microtubule interfering agents (MIA) and aryl-3-(2-chloroethyl)ureas (CEU) acting as antimitotics, along with CEU that don’t affect directly microtubules (non-MIA CEU). METHODS. To ascertain the activated signaling pathway profile of MIA and non-MIA CEU, Western blot, immunoprecipitation and transfection experiments were performed. RESULTS. Non-MIA CEU do not activate p38, as opposed to MIA, and the extent of ERK and JNK activation is lower than in response to MIA. The effect of MIA and non-MIA CEU on focal adhesion associated protein was also studied; MIA were shown to induce focal adhesion dismantlement associated with a sustained increase in paxillin phosphorylation and FAK cleavage, as opposed to non-MIA CEU. In addition, bcl-2 phosphorylation and AKT cleavage, induced by all MIA tested, was not observed in response to non-MIA CEU further emphasizing the differential cell death mechanisms induced by MIA and non-MIA CEU. Pharmacologic and genetic approaches emphasize that the ASK1-p38 pathway activation contributes to the cytotoxic mechanism of MIA, in contrast to non-MIA CEU. ASK1-p38 is important for increased paxillin phosphorylation and FAK cleavage, suggesting that ASK-1-p38 is an upstream event of FA structure dismantlement induced by MIA. Moreover, the endogen inhibitor of ASK-1, thioredoxin, is released from ASK-1 in response to MIA as opposed to non-MIA CEU. CONCLUSION. Our study supports that ASK1-p38 activation is an important signaling event, induced by MIA, which impairs focal adhesion structure and induces anchorage-dependent apoptosis or anoikis.

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Author Biographies

Jessica S Fortin, University of Arizona

College of pharmacy, University of Arizona, PO Box 210207, 1703 E. Mabel, Tucson, AZ, 85721

René C.-Gaudreault, Unité de Biotechnologie et de Bioingénierie

Faculté de médecine, Université Laval, Sainte-Foy, Québec, Canada, G1V 0A6

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Published

2010-06-07

How to Cite

Fortin, J. S., Patenaude, A., Deschesnes, R. G., Côté, M.-F., Petitclerc, E., & C.-Gaudreault, R. (2010). ASK1-P38 Pathway is Important for Anoikis Induced by Microtubule-Targeting Aryl Chloroethylureas. Journal of Pharmacy & Pharmaceutical Sciences, 13(2), 175–190. https://doi.org/10.18433/J31G6C

Issue

Section

Pharmaceutical Sciences; Review Articles