The mTORC1/S6K/PDCD4/eIF4A Axis Determines Outcome of Mitotic Arrest
Mohamed Moustafa-Kamal,
Thomas J. Kucharski,
Wissal El-Assaad,
Yazan M. Abbas,
Valentina Gandin,
Bhushan Nagar,
Jerry Pelletier,
Ivan Topisirovic,
Jose G. Teodoro
Affiliations
Mohamed Moustafa-Kamal
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Thomas J. Kucharski
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Wissal El-Assaad
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada
Yazan M. Abbas
Department of Biochemistry, McGill University, Montréal, QC, Canada
Valentina Gandin
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA
Bhushan Nagar
Department of Biochemistry, McGill University, Montréal, QC, Canada
Jerry Pelletier
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada
Ivan Topisirovic
Department of Biochemistry, McGill University, Montréal, QC, Canada; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, and Department of Oncology, McGill University, Montréal, QC, Canada; Corresponding author
Jose G. Teodoro
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada; Department of Biochemistry, McGill University, Montréal, QC, Canada; Corresponding author
Summary: mTOR is a serine/threonine kinase and a master regulator of cell growth and proliferation. Raptor, a scaffolding protein that recruits substrates to mTOR complex 1 (mTORC1), is known to be phosphorylated during mitosis, but the significance of this phosphorylation remains largely unknown. Here we show that raptor expression and mTORC1 activity are dramatically reduced in cells arrested in mitosis. Expression of a non-phosphorylatable raptor mutant reactivates mTORC1 and significantly reduces cytotoxicity of the mitotic poison Taxol. This effect is mediated via degradation of PDCD4, a tumor suppressor protein that inhibits eIF4A activity and is negatively regulated by the mTORC1/S6K pathway. Moreover, pharmacological inhibition of eIF4A is able to enhance the effects of Taxol and restore sensitivity in Taxol-resistant cancer cells. These findings indicate that the mTORC1/S6K/PDCD4/eIF4A axis has a pivotal role in the death versus slippage decision during mitotic arrest and may be exploited clinically to treat tumors resistant to anti-mitotic agents.
