Abstract
Cells experiencing delays in mitotic progression are prone to undergo apoptosis unless they can exit mitosis before proapoptotic factors reach a critical threshold. Microtubule targeting agents (MTAs) arrest cells in mitosis and induce apoptotic cell death engaging the BCL2 network. Degradation of the antiapoptotic BCL2 family member MCL-1 is considered to set the time until onset of apoptosis upon MTA treatment. MCL1 degradation involves its interaction with one of its key binding partners, the proapoptotic BH3-only protein NOXA. Here, we report that the mitochondria-associated E3-ligase MARCH5, best known for its role in mitochondrial quality control and regulation of components of the mitochondrial fission machinery, controls the levels of MCL1/NOXA protein complexes in steady state as well as during mitotic arrest. Inhibition of MARCH5 function sensitizes cancer cells to the proapoptotic effects of MTAs by the accumulation of NOXA and primes cancer cells that may undergo slippage to escape death in mitosis to cell death in the next G1 phase. We propose that inhibition of MARCH5 may be a suitable strategy to sensitize cancer cells to antimitotic drug treatment.
Highlights
Paclitaxel (Taxol) is a well-established anticancer therapeutic used to treat ovarian, breast, and a series of other cancers since the early 1990s [1]
As a so-called microtubule targeting agent (MTA), paclitaxel interferes with microtubule dynamics and at higher concentrations leads to stabilization of microtubules [2]
We show that co-depletion of NOXA, but not BIM, can restore the viability of the cells after MTA treatment
Summary
Paclitaxel (Taxol) is a well-established anticancer therapeutic used to treat ovarian, breast, and a series of other cancers since the early 1990s [1]. Other pro-survival proteins like BCL2, BCLX [9, 10], or BCLW [11] co-define life-span upon mitotic arrest. Their function seems to be limited by posttranslational modifications [12] and sequestration by proapoptotic BH3-only proteins like BIM [13] rather than degradation. Regulation of MCL1 stability during mitosis is an important aspect of mitotic arrest and defines the susceptibility of cancer cells to MTA treatment. We addressed the role of MARCH5 in regulating MCL1 levels and show that MARCH5 deficiency increases the stability of MCL1 during early mitotic arrest. Inhibition of MARCH5 can be considered as a strategy to increase the efficacy of MTAs
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