New research at the GCRC shines a light on drugs targeting mitosis which are frontline therapies for several cancers.
Lead author Moustafa-Kamal and his team demonstrate that the activity of the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream effectors regulates the outcome of mitotic arrest caused by drugs that target mitosis. This finding is critically important as it may indeed affect the course of cancer treatment in the future.
Research 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.
Read the full study here:
(This research was a collaboration between the laboratory of the GCRC’s Dr Teodoro and that of Dr Topisirovic at the Lady Davis Institute.)
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